Substituted pyrrolo-pyrazole derivatives as kinase inhibitors

ABSTRACT

Compounds represented by formula (Ia) or (Ib) and wherein R and R 1  are as defined in the description, and pharmaceutically acceptable salts thereof, are disclosed; the said compounds are useful in the treatment of cell cycle proliferative disorders, e.g. cancer, associated with an altered cell cycle dependent kinase activity.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. patent application, Ser. No. 10/539,145,filed May 4, 2006, which is a national stage filing, under 35 U.S.C.§371, of International application, Ser. No. PCT/EP2003/050942, filedDec. 4, 2003, which claims benefit from U.S. provisional patentapplication, Ser. No. 60/434,952, filed Dec. 19, 2002.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to pyrrolo-pyrazole derivatives, to aprocess for their preparation, to pharmaceutical compositions comprisingthem, and to their use as therapeutic agents, particularly in thetreatment of cancer and cell proliferation disorders.

2. Discussion of the Background

Several cytotoxic drugs such as, e.g., fluorouracil (5-FU), doxorubicinand camptothecins, damage DNA or affect cellular metabolic pathways andthus cause, in many cases, an indirect block of the cell cycle.Therefore, by producing an irreversible damage to both normal and tumorcells, these agents result in a significant toxicity and side-effects.

In this respect, compounds capable of functioning as highly specificantitumor agents by selectively leading to tumor cell arrest andapoptosis, with comparable efficacy but reduced toxicity than thecurrently available drugs, are desirable.

It is well known that progression through the cell cycle is governed bya series of checkpoint controls, otherwise referred to as restrictionpoints, which are regulated by a family of enzymes known as theCyclin-dependent kinases (Cdk). In turn, the Cdks themselves areregulated at many levels such as, for instance, binding to cyclins.

The coordinated activation and inactivation of different Cdk/Cyclincomplexes is necessary for normal progression through the cell cycle.Both the critical G1-S and G2-M transitions are controlled by theactivation of different Cdk/Cyclin activities. In G1, both Cdk4/Cyclin Dand Cdk2/Cyclin E are thought to mediate the onset of S-phase.Progression through S-phase requires the activity of Cdk2/Cyclin Awhereas the activation of Cdc2/Cyclin A (Cdk1) and Cdc2/cyclin B arerequired for the onset of mitosis. For a general reference to cyclinsand cyclin-dependent kinases see, for instance, Kevin R. Webster et al,in Exp. Opin. Invest. Drugs, 1998, Vol. 7(6), 865-887.

Checkpoint controls are defective in tumor cells due, in part, todisregulation of cdk activity. For example, altered expression of cyclinE and cdks has been observed in tumor cells, and deletion of the cdkinhibitor p27 KIP gene in mice has been shown to result in a higherincidence of cancer.

Increasing evidence supports the idea that the cdks are rate-limitingenzymes in cell cycle progression and, as such, represent moleculartargets for therapeutic intervention. In particular, the directinhibition of cdk/cyclin kinase activity should be helpful inrestricting the unregulated proliferation of a tumor cell.

SUMMARY OF THE INVENTION

It is an object of the invention to provide compounds which are usefulin treating cell proliferative disorders caused by and/or associatedwith an altered cell cycle dependent kinase activity. It is anotherobject to provide compounds which have cdk/cyclin kinase inhibitoryactivity.

The present inventors have now discovered that certain pyrazolecompounds are endowed with cdk/cyclin kinase inhibitory activity and arethus useful in therapy as antitumor agents and lack, in terms of bothtoxicity and side effects, the aforementioned drawbacks associated withcurrently available antitumor drugs.

More specifically, the pyrazole derivatives of the invention are usefulin the treatment of a variety of cancers including, but not limited to:carcinoma such as bladder, breast, colon, kidney, liver, lung, includingsmall cell lung cancer, esophagus, gall-bladder, ovary, pancreas,stomach, cervix, thyroid, prostate, and skin, including squamous cellcarcinoma; hematopoietic tumors of lymphoid lineage including leukaemia,acute lymphocitic leukaemia, acute lymphoblastic leukaemia, B-celllymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma,hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors ofmyeloid lineage, including acute and chronic myelogenous leukemias,myelodysplastic syndrome and promyelocytic leukaemia; tumors ofmesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumorsof the central and peripheral nervous system, including astrocytomaneuroblastoma, glioma and schwannomas; other tumors, including melanoma,seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum,keratoxanthoma, thyroid follicular cancer and Kaposi's sarcoma.

Due to the key role of cdks in the regulation of cellular proliferation,these pyrazole derivatives are also useful in the treatment of a varietyof cell proliferative disorders such as, for example, benign prostatehyperplasia, familial adenomatosis polyposis, neurofibromatosis,psoriasis, vascular smooth cell proliferation associated withatherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis andpost-surgical stenosis and restenosis.

The compounds of the invention may be useful in treatment of Alzheimer'sdisease, as suggested by the fact that cdk5 is involved in thephosphorylation of tau protein (J. Biochem. 117, 741-749, 1995).

The compounds of this invention, as modulators of apoptosis, may also beuseful in the treatment of cancer, viral infections, prevention of AIDSdevelopment in HIV-infected individuals, autoimmune diseases andneurodegenerative disorders.

The compounds of this invention may be useful in inhibiting tumorangiogenesis and metastasis, as well as in the treatment of organtransplant rejection and host versus graft disease.

The compounds of the invention may also act as inhibitor of otherprotein kinases, e.g., protein kinase C in different isoforms, Met,PAK-4, PAK-5, ZC-1, STLK-2, DDR-2, Aurora 1, Aurora 2, Bub-1, PLK, Chk1,Chk2, HER2, raf1, MEK1, MAPK, EGF-R, PDGF-R, FGF-R, IGF-R, PI3K, weelkinase, Src, Abl, Akt, MAPK, ILK, MK-2, IKK-2, Cdc7, Nek, and thus beeffective in the treatment of diseases associated with other proteinkinases.

The compounds of the invention are also useful in the treatment andprevention of radiotherapy-induced or chemotherapy-induced alopecia.

Accordingly, the present invention provides a method for treating cellproliferative disorders caused by and/or associated with an altered cellcycle dependent kinase activity, by administering to a mammal in needthereof an effective amount of a pyrazole derivative represented byformula (Ia) or (Ib)

wherein,

-   R is a group —COR^(a), —CONHR^(a) or —CONR^(a)R^(b) wherein R^(a)    and R^(b) are, each independently, hydrogen or an optionally    substituted group selected from straight or branched C₁-C₆ alkyl,    C₃-C₆ cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl    or; together with the nitrogen atom to which they are bonded, R^(a)    and R^(b) may form an optionally substituted 5 or 6 membered    heterocycle optionally containing one additional heteroatom or    heteroatomic group selected among N, NH, O or S;-   R₁ is selected from the group consisting of:-   a) straight or branched C₃-C₄ alkyl;-   b) cycloalkyl, cycloalkyl-alkyl or alkyl-cycloalkyl wherein the    cycloalkyl moiety comprises any C₃-C₆ cycloalkyl group and wherein    the alkyl moiety comprises any straight or branched C₁-C₄ alkyl    group:-   c) 3-methylthienyl-2-yl; 2-thienyl; phenyl; 2,6-difluorophenyl;    4-(aminosulfonyl)phenyl; 4-(dimethylaminomethyl)phenyl;    4-(4-methylpiperazinyl)methylphenyl;-   d) a group of formula (IIa) or (IIb):

wherein, in formula (IIa), the cycle represents a 5 to 7 memberedheterocyclic ring wherein X, directly linked to the rest of themolecule, represents a carbon or nitrogen atom; Y is a carbon, nitrogen,oxygen or sulfur atom or it is an NH group, provided that at least oneof X and Y is other than a carbon atom; R^(c) is, independently fromeach other and in any one of the free positions of the heterocyclic ringof formula (IIa), a halogen atom or hydroxy group or it is an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl, C₃-C₆cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, amino,aminocarbonyl, carboxy, oxo (═O), alkoxycarbonyl, alkylcarbonyl orarylcarbonyl; and n is 0 or an integer from 1 to 4;

-   e) a group of formula (IIc) or (IId):

wherein R^(d), R′^(d) and R^(e) represent, the same or different andindependently from each other, a hydrogen atom or a straight or branchedC₁-C₆ alkyl optionally substituted by one or more groups selected fromhydroxy (—OH), aminocarbonyl (—CONH₂) or methylaminocarbonyl (—CONHCH₃);provided that in formula (Ia), when R₁ is a group of formula (IIc) andone of R^(d) or R′^(d) is a hydrogen atom whilst the other of R^(d) orR′^(d) is ethyl or n-butyl, then R is other than —COR^(a) with R^(a) as3-bromophenyl, benzyl, 4-tert-butylphenyl, 4-tert-butylphenylmethyl,4-fluorophenylmethyl, cyclopropyl or 2-naphthylmethyl;or a pharmaceutically acceptable salt thereof.

In a preferred embodiment of the method described above, the cellproliferative disorder is selected from the group consisting of cancer,Alzheimer's disease, viral infections, autoimmune diseases andneurodegenerative disorders.

Specific types of cancer that may be treated include carcinoma, squamouscell carcinoma, hematopoietic tumors of myeloid or lymphoid lineage,tumors of mesenchymal origin, tumors of the central and peripheralnervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma,xeroderma pigmentosum, keratoxanthoma, thyroid follicular cancer, andKaposi's sarcoma.

In another preferred embodiment of the method described above, the cellproliferative disorder is selected from the group consisting of benignprostate hyperplasia, familial adenomatosis polyposis,neuro-fibromatosis, psoriasis, vascular smooth cell proliferationassociated with atherosclerosis, pulmonary fibrosis, arthritis,glomerulonephritis and post-surgical stenosis and restenosis. Inaddition, the inventive method provides tumor angiogenesis andmetastasis inhibition as well as treatment of organ transplant rejectionand host versus graft disease. The inventive method may also providecell cycle inhibition or cdk/cyclin dependent inhibition.

In addition to the above, the method object of the present inventionprovides treatment and prevention of radiotherapy-induced orchemotherapy-induced alopecia.

The present invention also provides a pyrazole derivative represented byformula (Ia) or (Ib)

wherein

-   R is a group COR^(a), —CONHR^(a) or —CONR^(a)R^(b) wherein R^(a) and    R^(b) are, each independently, hydrogen or an optionally substituted    group selected from straight or branched C₁-C₆ alkyl, C₃-C₆    cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or;    together with the nitrogen atom to which they are bonded, R^(a) and    R^(b) may form an optionally substituted 5 or 6 membered heterocycle    optionally containing one additional heteroatom or heteroatomic    group selected among N, NH, O or S;-   R₁ is selected from the group consisting of:-   a) straight or branched C₃-C₄ alkyl;-   b) cycloalkyl, cycloalkyl-alkyl or alkyl-cycloalkyl wherein the    cycloalkyl moiety comprises any C₃-C₆ cycloalkyl group and wherein    the alkyl moiety comprises any straight or branched C₁-C₄ alkyl    group:-   c) 3-methylthienyl-2-yl; 2-thienyl; phenyl; 2,6-difluorophenyl;    4-(aminosulfonyl)phenyl; 4-(dimethylaminomethyl)phenyl;    4-(4-methylpiperazinyl)methylphenyl;-   d) a group of formula (IIa) or (IIb):

wherein, in formula (IIa), the cycle represents a 5 to 7 memberedheterocyclic ring wherein X, directly linked to the rest of themolecule, represents a carbon or nitrogen atom; Y is a carbon, nitrogen,oxygen or sulfur atom or it is an NH group, provided that at least oneof X and Y is other than a carbon atom; R^(c) is, independently fromeach other and in any one of the free positions of the heterocyclic ringof formula (IIa), a halogen atom or hydroxy group or it is an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl, C₃-C₆cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, amino,aminocarbonyl, carboxy, oxo (═O), alkoxycarbonyl, alkylcarbonyl orarylcarbonyl; and n is 0 or an integer from 1 to 4;

-   e) a group of formula (IIc) or (IId):

wherein R^(d), R′^(d) and R^(e) represent, the same or different andindependently from each other, a hydrogen atom or a straight or branchedC₁-C₆ alkyl optionally substituted by one or more groups selected fromhydroxy (—OH), aminocarbonyl (—CONH₂) or methylaminocarbonyl (—CONHCH₃);

-   provided that in formula (Ia), when R₁ is a group of formula (IIc)    and one of R^(d) or R′^(d) is a hydrogen atom whilst the other of    R^(d) or R′^(d) is ethyl or n-butyl, then R is other than —COR^(a)    with R^(a) as 3-bromophenyl, benzyl, 4-tert-butylphenyl,    4-tert-butylphenylmethyl, 4-fluorophenylmethyl, cyclopropyl or    2-naphthylmethyl;    or a pharmaceutically acceptable salt thereof.

The present invention also includes methods for the synthesis of thepyrazole derivatives represented by formulae (Ia) or (Ib) that, unlessotherwise provided, may be conveniently grouped and defined as compoundsof formula (I). Pharmaceutical compositions comprising the pyrazolederivatives of formula (I) are also included in the present invention.

A more complete appreciation of the invention and many of the attendantadvantages thereof will be readily obtained as the same becomes betterunderstood by reference to the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Several heterocyclic compounds are known in the art as protein kinaseinhibitors. As an example, 2-carboxamido-pyrazoles and2-ureido-pyrazoles, and derivatives thereof, have been disclosed asprotein kinase inhibitors in the international patent applications WO01/12189, WO 01/12188, WO 02/48114 and WO 02/70515, all in the name ofthe applicant itself.

Fused bicyclic compounds comprising pyrazole moieties and possessingkinase inhibitory activity have been also disclosed in WO 00/69846 andWO 02/12242 as well as in WO 03/028720 (PCT/EP02/10534 claiming priorityfrom U.S. patent application Ser. No. 09/962,162 of Sep. 26, 2001) andcopending PCT/EP03/04862 (claiming priority from U.S. patent application60/381,092 of May 17, 2002), all in the name of the applicant itself.

The compounds object of the present invention fall within the scope ofthe general formula of the aforementioned WO 02/12242, herewithincorporated by reference, but are not specifically exemplified therein.

Unless otherwise specified, when referring to the compounds of formula(I) per se as well as to any pharmaceutical composition thereof or toany therapeutic treatment comprising them, the present inventionincludes all of the hydrates, solvates, complexes, metabolites andprodrugs of the compounds of this invention. Prodrugs are any covalentlybonded compounds, which release the active parent drug according toformula (I) in vivo.

A metabolite of a compound of formula (I) is any compound into whichthis same compound of formula (I) is converted, in vivo, for instanceupon administration to a mammal in need thereof.

Typically, without however representing a limiting example, uponadministration of a compound of formula (I), this same derivative may beconverted into a variety of compounds, for instance including moresoluble derivatives like hydroxylated derivatives, which are easy to beexcreted. Hence, depending upon the metabolic pathway thus occurring,any of these hydroxylated derivatives may be regarded as a metabolite ofthe compounds of formula (I).

If a chiral center or another form of an isomeric center is present in acompound of the present invention, all forms of such isomer or isomers,including enantiomers and diastereomers, are intended to be coveredherein. Compounds containing a chiral center may be used as a racemicmixture, an enantiomerically enriched mixture, or the racemic mixturemay be separated using well-known techniques and an individualenantiomer may be used alone. In cases in which compounds haveunsaturated carbon-carbon double bonds, both the cis (Z) and trans (E)isomers are within the scope of this invention. In cases whereincompounds may exist in tautomeric forms, such as keto-enol tautomers,each tautomeric form is contemplated as being included within thisinvention whether existing in equilibrium or predominantly in one form.

In the present description, unless otherwise specified, with the termstraight or branched C₁-C₆ alkyl, hence comprehensive of C₁-C₄ alkyl, weintend any of the groups such as, for instance, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl,and the like.

With the term C₃-C₆ cycloalkyl we intend, unless otherwise provided, acycloaliphatic ring such as cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

The term aryl includes carbocyclic or heterocyclic hydrocarbons withfrom 1 to 2 ring moieties, either fused or linked to each other bysingle bonds, wherein at least one of the rings is aromatic; if present,any aromatic heterocyclic hydrocarbon also referred to as heteroarylgroup, comprises a 5 to 6 membered ring with from 1 to 3 heteroatoms orheteroatomic groups selected among N, NH, O or S.

Examples of aryl groups according to the invention are, for instance,phenyl, biphenyl, α- or β-naphthyl, dihydronaphthyl, thienyl,benzothienyl, furyl, benzofuranyl, pyrrolyl, imidazolyl, pyrazolyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, indolyl, isoindolyl, purinyl, quinolyl,isoquinolyl, dihydroquinolinyl, quinoxalinyl, benzodioxolyl, indanyl,indenyl, triazolyl, and the like.

Unless otherwise specified, the term heterocycle or heterocyclylincludes 5 to 6 membered saturated, partly unsaturated or fullyunsaturated heterocycles with from 1 to 3 heteroatoms or heteroatomicgroups selected among N, NH, O or S.

Apart from the fully unsaturated heterocycles, previously referred to asaromatic heterocycles and encompassed by the term aryl, examples ofsaturated or partly unsaturated heterocycles according to the inventionare, for instance, pyran, pyrrolidine, pyrroline, imidazoline,imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine,dihydrofuran, tetrahydrofuran, 1,3-dioxolane, piperidine, piperazine,morpholine and the like.

When referring to the compounds of the invention wherein R₁ is groupedunder (b), R₁ itself may represent a given cycloalkyl group, forinstance cyclopropyl; a given cycloalkyl-alkyl group, for instancecyclopropylmethyl; or even a given alkyl-cycloalkyl group, for instancemethylcyclopropyl; all of which have the following formulae:

When referring to the compounds of the invention wherein R₁ is a groupof formula (IIa), the 5 to 7 membered heterocyclic ring is directlylinked to the rest of the molecule through the X atom, as follows:

Examples of these 5 to 7 membered heterocycles include any 5 to 6membered heterocycle among those already reported and, additionally, 7membered heterocycles such as, for instance, azepine, diazepine,oxazepine and the like.

Any R^(c), if present, is at any one of the free positions of theheterocyclic ring of formula (IIa) by replacement of a hydrogen atom.

When referring to the compounds of the invention wherein R₁ is a groupof formula (IIc) or (IId), ureido and carbamate derivatives may be thusidentified, having the following sub-formulae:

According to the present invention and unless otherwise provided, any ofthe above R^(a), R^(b) and R^(c) groups may be optionally substituted,in any of their free positions, by one or more groups, for instance 1 to6 groups, independently selected from: halogen, nitro, oxo groups (═O),cyano, alkyl, polyfluorinated alkyl, polyfluorinated alkoxy, alkenyl,alkynyl, hydroxyalkyl, aryl, arylalkyl, heterocyclyl, cycloalkyl,hydroxy, alkoxy, aryloxy, heterocyclyloxy, methylenedioxy,alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, alkylideneaminooxy,carboxy, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, amino,ureido, alkylamino, dialkylamino, arylamino, diarylamino, formylamino,alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino,alkoxycarbonylamino, alkoxyimino, alkylsulfonylamino, arylsulfonylamino,formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl,heterocyclylcarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylthio and alkylthio.

In this respect, with the term halogen atom we intend a fluorine,chlorine, bromine or iodine atom.

With the term alkenyl or alkynyl we intend any of the aforementionedstraight or branched C₂-C₆ alkyl groups further bearing a double ortriple bond. Non limiting examples of alkenyl or alkynyl groups of theinvention are, for instance, vinyl, allyl, 1-propenyl, isopropenyl,1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1-hexenyl, ethynyl,2-propynyl, 4-pentynyl, and the like.

With the term polyfluorinated alkyl or alkoxy we intend any of the abovestraight or branched C₁-C₆ alkyl or alkoxy groups which are substitutedby more than one fluorine atom such as, for instance, trifluoromethyl,trifluoroethyl, 1,1,1,3,3,3-hexafluoropropyl, trifluoromethoxy and thelike.

With the term alkoxy, aryloxy, heterocyclyloxy and derivatives thereofwe intend any of the above alkyl, aryl or heterocyclyl groups linked tothe rest of the molecule through a oxygen atom (—O—).

From all of the above, it is clear to the skilled person that any groupwhich name is a composite name such as, for instance, cycloalkylalkyl,arylalkyl, heterocyclylalkyl, alkoxy, alkylthio, aryloxy, arylalkyloxy,alkylcarbonyloxy, arylalkyl, heterocyclylalkyl and the like, have to beintended as conventionally construed by the parts from which theyderive. As an example, a group such as heterocyclylalkyloxy is an alkoxygroup, e.g. alkyloxy, wherein the alkyl moiety is further substituted bya heterocyclyl group, and wherein alkyl and heterocyclyl are as abovedefined.

Pharmaceutically acceptable salts of the compounds of formula (I)include the acid addition salts with inorganic or organic acids, e.g.,nitric, hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric,acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, malonic,malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic,methanesulphonic, isethionic and salicylic acid. Preferably, the acidaddition salt of the compounds of the invention is selected between thehydrochloride or mesylate salt.

Pharmaceutically acceptable salts of the compounds of formula (I) alsoinclude the salts with inorganic or organic bases, e.g., alkali oralkaline-earth metals, especially sodium, potassium, calcium ormagnesium hydroxides, carbonates or bicarbonates, acyclic or cyclicamines, preferably methylamine, ethylamine, diethylamine, triethylamine,piperidine and the like.

A first class of preferred compounds of formula (Ia) or (Ib) isrepresented by the derivatives wherein R is a group COR^(a), R^(a) is asabove defined and R₁ is tert-butyl.

Another class of preferred compounds of formula (Ia) or (Ib) isrepresented by the derivatives wherein R is a group —CONHR^(a), R^(a) isas above defined and R₁ is tert-butyl.

Another class of preferred compounds of formula (Ia) or (Ib) isrepresented by the derivatives wherein R is a group —CONR^(a)R^(b),R^(a) and R^(b) are as above defined and R₁ is tert-butyl.

Another class of preferred compounds of formula (Ia) or (Ib) isrepresented by the derivatives wherein R is as above defined and R₁ is agroup of formula (Ia) selected from:

wherein R^(c) has the above reported meanings.

Another class of preferred compounds of formula (Ia) or (Ib) isrepresented by the derivatives wherein R is as above defined and R₁ is agroup of formula (Ia) selected from:

wherein n and R^(c) have the above reported meanings.

Particularly preferred, within the above classes, are the compounds offormula (Ia) wherein R is a group —COR^(a) with R^(a) as 4-fluorophenylor cyclobutyl, and R₁ is as defined in the general formula.

Also particularly preferred are the compounds of formula (Ia) wherein Ris as defined in the general formula, and R₁ is a group selected fromtert-butyl, 1-methyl-piperidyl-4-yl, 1-methyl-piperazinyl-4-yl,2-(R,S)-tetrahydrofuranyl-2-yl, 2-(R)-tetrahydrofuranyl-2-yl or2-(S)-tetrahydrofuranyl-2-yl.

For a general reference to any specific compound of formula (I) of theinvention, optionally in the form of a pharmaceutically acceptable salt,see the experimental section.

As formerly indicated, a further object of the present invention isrepresented by the process for preparing the compounds of formula (I).

Therefore, the compounds of formula (I) and the pharmaceuticallyacceptable salts may be obtained by a process comprising:

-   a) reacting a compound of formula (IIIa) or (IIIb)

with acrylonitrile so as to obtain the corresponding derivative offormula (IVa) or (IVb)

b) protecting the amino group of the compound of formula (IVa) or (IVb)so as to obtain the corresponding derivative of formula (Va) or (Vb)

wherein Q is a suitable amino protecting group;

-   c) reacting the compound of formula (Va) or (Vb) with a suitable    alkylating agent so as to obtain the corresponding ester derivative    of formula (VIa) or (VIb)

wherein Alk stands for a suitable C₁-C₄ alkyl group;

-   d) reacting the compound of formula (VIa) or (VIb) with sodium    hydride (NaH) so as to obtain the corresponding derivative of    formula (VIIa) or (VIIb)

e) reacting the compound of formula (VIIa) or (VIIb) with hydrazinehydrate so as to obtain the compound of formula (VIIIa) or (VIIIb)

f) reacting the compound of formula (VIIIa) or (VIIIb) with ethylchloroformate so as to obtain the derivative of formula (IXa) or (IXb),each one in any of the two regioisomeric forms

and reacting the compounds of formula (IXa) or (IXb) according to anyone of the alternative steps (g.1), (g.2) or (g.3)

-   g.1) with a compound of formula (X)    R^(a)CO-Z  (X)    wherein R^(a) is as above defined and Z is a halogen atom, so as to    obtain the compound of formula (XIa) or (XIb)

wherein R is a group —COR^(a);

-   g.2) with a compound of formula (XII)    R^(a)—NCO  (XII)    wherein R^(a) is as above defined so as to obtain the compound of    the formula (XIa) or (XIb) wherein R is a group —CONHR^(a); or-   g.3) with a suitable amine of formula (XIII) in the presence of    triphosgene or of a suitable chloroformate    HNR^(a)R^(b)  (XIII)    wherein R^(a) and R^(b) are as above defined, so as to obtain the    compound of formula (XIa) or (XIb) wherein R is a group    —CONR^(a)R^(b);-   h) deprotecting the amino group of the compound of formula (XIa) or    (XIb) prepared according to any one of steps from (g.1) to (g.3), so    as to obtain the corresponding derivative of formula (XIVa) or    (XIVb)

wherein R has the above reported meanings; and reacting the compound offormula (XIVa) or (XIVb) according to any one of the alternative steps(i.1), (i.2), (i.3) or (i.4)

-   i.1) with an acyl halide derivative of formula (XV)    R₁—COZ  (XV)    wherein R₁ is as set forth in formula (Ia) or (Ib) under groups (a),    (b), (c), (IIa) with X as a carbon atom and (IIb), and Z is a    halogen atom, so as to obtain a compound of formula (XVIa) or (XVIb)

wherein R and R₁ are as above defined;

-   i.2) with a 5 to 7 membered heterocyclic compound of formula (XVII)    or a suitable amine of formula (XVIII), in the presence of    triphosgene

wherein X is NH and Y, R^(c), n, R^(d) and R′^(d) have the abovereported meanings, so as to obtain the corresponding compounds offormula (XVIa) or (XVIb) wherein R is as above defined and R₁ is eithera group of formula (IIa) with X as a nitrogen atom and R, Y, R^(c) and nas above defined, or of formula (IIc) wherein R^(d) and R′^(d) are asabove defined;

-   i.3) with a carboxylic acid of formula (XIX) in the presence of a    suitable condensing agent    R₁—COOH  (XIX)    so as to obtain a compound of formula (XVIa) or (XVIb) wherein R₁ is    as set forth in formula (Ia) or (Ib) under groups (a), (b), (c) or    it is a group of formula (IIa) with X as a carbon atom or of formula    (IIb), and R, Y, R^(c) and n are as above defined;-   i.4) with a compound of formula (XX)    R₁—COZ  (XX)    wherein R₁ is a group of formula (IId) and Z is a chlorine or    bromine atom, so as to obtain the a compound of formula (XVIa) or    (XVIb) wherein R is as defined above and R₁ is a group of formula    (IId); and-   j) reacting the compound of formula (XVIa) or (XVIb) prepared    according to any one of steps from (i.1) to (i.4) under basic    conditions, so as to obtain the corresponding derivative of formula    (Ia) or (Ib) wherein R and R₁ are as above defined; and, optionally,-   k) converting them into other compounds of formula (Ia) or (Ib),    respectively, and/or into pharmaceutically acceptable salts thereof.

The above process is an analogy process which can be carried outaccording to methods well known in the art.

From all of the above, it is clear to the person skilled in the art thatif a compound of formula (Ia) or (Ib), prepared according to the aboveprocess, is obtained as a mixture of isomers, their separation into thesingle isomers of formula (Ia) or (Ib), carried out according toconventional techniques, is still within the scope of the presentinvention.

Likewise, the conversion into the free compound (Ia) or (Ib) of acorresponding salt thereof, according to well-known methods, is stillwithin the scope of the invention.

According to step (a) of the process, a compound of formula (IIIa) or(IIIb) is reacted with acrylonitrile in the presence of a suitable base,for instance sodium hydroxide. The reaction is preferably carried out inwater at a temperature ranging from about −10° C. to room temperature.

According to step (b) of the process, the amino group of the compound offormula (IVa) or (IVb) is protected according to conventional methods,for instance with tert-butoxycarbonyl anhydride (Boc₂O) and in thepresence of a suitable solvent such as acetonitrile or dichloromethane,so as to get the corresponding derivative of formula (Va) or (Vb)wherein the amino protecting group Q just represents tert-butoxycarbonyl(boc).

According to step (c) of the process, the carboxy group of the compoundof formula (Va) or (Vb) is converted into the corresponding alkyl esterderivative, for instance by operating in the presence of a suitablealkyl halide, for instance methyl iodide.

The reaction is carried out in the presence of a suitable solvent suchas dimethylformamide and under basic conditions, for instance by usingsodium or potassium hydrogencarbonate. According to step (d) of theprocess, the compound of formula (VIa) or (VIb) is converted into thecorresponding cyclic derivative of formula (VIIa) or (VIIb) throughreaction with sodium hydride. The reaction is carried out in thepresence of a suitable solvent such as dioxane or tetrahydrofuran atrefluxing temperature.

According to step (e) of the process, the compound of formula (VIIa) or(VIIb) is reacted with hydrazine hydrate, preferably with an excess ofhydrazine monohydrated, for instance up to 10 equivalents, in thepresence of a suitable solvent such as halogenated hydrocarbons, loweralcohols or admixtures thereof. The reaction is preferably carried outin the presence of ethanol, by adding hydrazine to a solution of thecompound of formula (VIIa) or (VIIb) and under stirring for a suitabletime, for instance about 48 hours, at the temperature ranging from about20° C. to about 70° C. Preferably, the above reaction is carried outalso in the presence of glacial acetic acid.

According to step (f) of the process, the compound of formula (VIIIa) or(VIIIb) is reacted with ethyl chloroformate so as to get thecorresponding derivative of formula (IXa) or (IXb). The reaction iscarried out according to well-known operative conditions, in thepresence of a suitable base, for instance diisopropylethylamine, and ofa suitable solvent such as tetrahydrofuran.

Clearly, the ethoxycarbonyl group may be bound to any one of thepyrazole nitrogen atoms of both compounds of formula (VIIIa) and (VIIIb)so as to give rise to the following regioisomers of formula (IXa) or(IXb)

In this respect, each couple of regioisomers of formula (IXa) or (IXb)may be conveniently separated according to well-known methods, forinstance under chromatographic conditions, and each regioisomer soisolated subsequently worked out. In the alternative, the mixture ofregioisomers can be treated as such in the subsequent steps of theprocess, without providing any separation.

In fact, as the ethoxycarbonyl group leading to two distinctregioisomers is finally removed at the end of the process, it is clearto the skilled person that both the above pathways can be carried outfor preparing the compounds of formula (Ia) or (Ib) of the invention.

Preferably, however, the process is carried out by first separating andisolating the regioisomers of formula (IXa) or (IXb) from their mixture,as reported in the working examples, and by subsequently reacting themto the desired compounds.

According to step (g.1) of the process, the compound of formula (IXa) or(IXb) is reacted with a suitable derivative of formula (X) wherein Zrepresents a halogen atom, preferably chlorine or bromine.

Typically, the compound of formula (IXa) or (IXb) is dissolved in asuitable solvent such as dichloromethane, dimethylformamide,tetrahydrofuran, dioxane or the like, and a suitable base such astriethylamine, diisopropylethylamine, sodium carbonate or the like isadded. The compound of formula (X) is then added and the mixture stirredfor a time of about 2 to about 15 hours, at a temperature ranging fromabout 20° C. to about 80° C.

A suitable catalyst such as dimethylamino-pyridine may be optionallyused.

According to step (g.2) of the process, the compound of formula (IXa) or(IXb) is reacted with an isocyanate derivative of formula (XII), byoperating substantially as set forth in step (g.1) of the process,except that the base may not be required.

According to step (g.3) of the process, the compound of formula (IXa) or(IXb) is reacted with an amine of formula (XIII) in the presence oftriphosgene or of a suitable chloroformate, for instance 4-nitrophenylchloroformate, so as to get the corresponding ureido derivative. Thereaction is carried out in tetrahydrofuran (THF) or in a suitablehalogenated hydrocarbon, preferably dichloromethane (DCM), and in thepresence of a suitable amine such as diisopropylethylamine ortriethylamine at a temperature ranging from about −70° C. to roomtemperature.

According to step (h) of the process, the protected amino group informula (XIa) or (XIb) is deprotected under well-known operativeconditions, for instance under acidic conditions in the presence oftrifluoroacetic or hydrochloric acid.

The compound of formula (XIa) or (XIb) is thus suspended in a suitablesolvent such as dichloromethane or dioxane, and treated with aconcentrated solution of the selected acid. Alternatively, commerciallyavailable solutions of gaseous hydrogen chloride dissolved in dioxane (4M HCl) may be advantageously employed. The mixture is then stirred for atime of about 2 hours to about 15 hours at a temperature ranging fromabout 20° C. to about 40° C.

According to any one of steps (i.1), (i.2), (i.3) or (i.4) of theprocess, the compound of formula (XIVa) or (XIVb) is further reactedwith a suitable derivative so as to obtain the correspondingcarboxamido, ureido or carbamate derivative of formula (XVIa) or (XVIb).Step (i.1) is carried out with an acyl halide, preferably chloride, offormula (XV) in a suitable solvent such as dichloromethane and underbasic conditions, for instance in the presence of a suitable amine suchas diisopropylethylamine.

The reaction allows to obtain carboxamido derivatives of formula (XVIa)or (XVIb) wherein R₁ is as defined in formula (I) under groups from (a)to (c), (IIa) with X as a carbon atom and (IIb); from the above, it isclear to the skilled person that the atom of the R₁ group which isdirectly linked to the carbonyl moiety of formula (XVIa) or (XVIb) is acarbon atom.

Step (i.2) is carried out with a heterocyclic derivative of formula(XVII) or of an amine of formula (XVIII), in the presence oftriphosgene, substantially as described under step (g.3) of the process.

In this respect, step (i.2) allows to obtain ureido derivatives offormula (XVIa) or (XVIb) wherein R₁ is a group of formula (IIa) with Xas a nitrogen atom or of formula (IIc) and wherein Y, R^(c), n, R^(d)and R′^(d) are as above defined.

Likewise, the condensation of step (i.3) is carried out with acarboxylic acid derivative of formula (XIX), in the presence of asuitable condensing agent such as, for instance,dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDC) or O-benzotriazolyltetramethylisouronium tetrafluoroborate (TBTU), and by operatingaccording to well-known methods for preparing carboxamido derivatives.

According to step (i.4) of the process, the compound of formula (XIVa)or (XIVb) is reacted with a suitable derivative of formula (XX) whereinR₁ is a group of formula (IId) and R^(e) is as set forth in formula (Ia)or (Ib), so as to obtain the corresponding carbamate derivatives offormula (XVIa) or (XVIb).

In this respect, the compound of formula (XIVa) or (XIVb) is dissolvedin a suitable solvent such as dichloromethane, dimethylformamide,tetrahydrofuran, dioxane or the like, and a suitable base such astriethylamine, diisopropylethylamine, sodium carbonate or the like isadded therein. The compound of general formula (XX) is then added andthe mixture stirred for a time of about 2 hours to about 15 hours, at atemperature ranging from about 20° C. to about 80° C. According to apreferred embodiment, a suitable catalyst such as dimethylamino pyridinemay be optionally used.

According to step (j) of the process, the compound of formula (XVIa) or(XVIb) being obtained in any one of steps from (i.1) to (i.4) is reactedwith a suitable base, for instance triethylamine, and in the presence ofa suitable solvent such as methanol or ethanol so as to obtain thedesired compound of formula (Ia) or (Ib).

Finally, as per step (k) of the process, these latter compounds (Ia) or(Ib) may be optionally converted into pharmaceutically acceptable saltsas formerly reported and by working according to conventional methodsor, alternatively, may converted into additional compounds of formula(Ia) or (Ib).

Just as a non limiting example, compounds of formula (Ia) or (Ib)bearing a carboxyester function may be converted into a variety ofderivatives according to methods well known in the art to convertcarboxyester groups into carboxamides, N-substituted carboxamides,N,N-disubstituted carboxamides, carboxylic acids, and the like.

The operative conditions are those widely known in the art and maycomprise, for instance in the conversion of a carboxyester group into acarboxamide group, the reaction with ammonia or ammonium hydroxide inthe presence of a suitable solvent such as a lower alcohol,dimethylformamide or mixtures thereof, preferably the reaction iscarried out with ammonium hydroxide in a methanol/dimethylformamidemixture, at a temperature ranging from about 50° C. to about 100° C.

Analogous operative conditions apply in the preparation of N-substitutedor N,N-disubstituted carboxamides wherein a suitable primary orsecondary amine is used in place of ammonia or ammonium hydroxide.

Likewise, carboxyester groups may be converted into carboxylic acidderivatives through basic or acidic hydrolysis conditions, widely knownin the art.

As an additional example, compounds of formula (Ia) or (Ib) bearing anamino function may be easily converted into the correspondingcarboxamido or ureido derivatives.

From all of the above it is clear to the skilled person that accordingto step (k) of the process, any compound of formula (Ia) or (Ib) bearinga functional group which can be further derivitized to anotherfunctional group, by working according to methods well known in the artthus leading to other compounds of formula (Ia) or (Ib), has to beintended as comprised within the scope of the present invention.

According to any variant of the process for preparing the compounds offormula (I), the starting material and any other reactant is known oreasily prepared according to known methods.

As an example, whilst the starting materials of formula (IIIa) or (IIIb)are commercially available, the compounds of formula (X), (XII), (XIII),(XV), (XVII), (XVIII), (XIX) and (XX) are known or can be easilyprepared according to known methods.

The intermediate compounds of formula (VIIa) or (VIIb) of the process

wherein Q represents a suitable nitrogen protecting group, for instancetert-butoxycarbonyl (boc), are novel and, hence, represent a furtherobject of the invention.

As it will be readily appreciated, if the compounds of formula (I)prepared according to the process described above are obtained as anadmixture of isomers, their separation into the single isomers offormula (I), according to conventional techniques, is within the scopeof the present invention. Conventional techniques for racemateresolution include, for instance, partitioned crystallization ofdiastereoisomeric salt derivatives or preparative chiral HPLC.

In addition, it is clear from the above that a given compound of formula(Ia) or (Ib) may be prepared either by starting from the mixture of theregioisomers of formula (IXa) or (IXb) or, alternatively, from each oneof the two regioisomers themselves.

When preparing the compounds of formula (I) according to any one of theaforementioned process variants, optional functional groups within thestarting materials or the intermediates thereof and which could giverise to unwanted side reactions, need to be properly protected accordingto conventional techniques. Likewise, the conversion of these latterinto the free deprotected compounds may be carried out according toknown procedures.

In addition, the compounds of formula (I) of the invention may be alsoprepared according to combinatorial chemistry techniques widely known inthe art, by accomplishing the aforementioned reactions between theseveral intermediates in a serial manner and by working undersolid-phase-synthesis (SPS) conditions.

As an example, the compounds of formula (XIa) or (XIb) which areprepared according to any one of steps (g.1), (g.2) or (g.3) can besupported onto a suitable polymeric resin. More particularly, theethoxycarbonyl group in formula (XIa) or (XIb) may be removed underbasic conditions, for instance in the presence of triethylamine ordiisopropylamine, and the resultant compound anchored to the abovesupporting resin, through the pyrazole nitrogen atom itself

The supported intermediate thus obtained may be then reacted accordingto step (h) and any one of steps (i.1), (i.2), (i.3) or (i.4) of theprocess, so as to obtain the corresponding compound of formula (Ia) or(Ib) of the invention still supported on the polymeric resin. Subsequentresin cleavage, for instance under basic or acidic conditions accordingto known methods, allows to obtain the desired compounds of formula (Ia)or (Ib).

Clearly, by performing the above reactions of the process in a serialmanner that is by following a combinatorial approach for instance as setforth above, several compounds of formula (Ia) and (Ib) may be thusprepared and collected.

Therefore, it is a further object of the present invention a library oftwo or more compounds of formula (Ia)

wherein

-   R is a group COR^(a), —CONHR^(a) or —CONR^(a)R^(b) wherein R^(a) and    R^(b) are, each independently, hydrogen or an optionally substituted    group selected from straight or branched C₁-C₆ alkyl, C₃-C₆    cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or;    together with the nitrogen atom to which they are bonded, R^(a) and    R^(b) may form an optionally substituted 5 or 6 membered heterocycle    optionally containing one additional heteroatom or heteroatomic    group selected among N, NH, O or S;-   R₁ is selected from the group consisting of:-   a) straight or branched C₃-C₄ alkyl;-   b) cycloalkyl, cycloalkyl-alkyl or alkyl-cycloalkyl wherein the    cycloalkyl moiety comprises any C₃-C₆ cycloalkyl group and wherein    the alkyl moiety comprises any straight or branched C₁-C₄ alkyl    group:-   c) 3-methylthienyl-2-yl; 2-thienyl; phenyl; 2,6-difluorophenyl;    4-(aminosulfonyl)phenyl; 4-(dimethylaminomethyl)phenyl;    4-(4-methylpiperazinyl)methylphenyl;-   d) a group of formula (IIa) or (IIb):

wherein, in formula (IIa), the cycle represents a 5 to 7 memberedheterocyclic ring wherein X, directly linked to the rest of themolecule, represents a carbon or nitrogen atom; Y is a carbon, nitrogen,oxygen or sulfur atom or it is an NH group, provided that at least oneof X and Y is other than a carbon atom; R^(c) is, independently fromeach other and in any one of the free positions of the heterocyclic ringof formula (IIa), a halogen atom or hydroxy group or it is an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl, C₃-C₆cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, amino,aminocarbonyl, carboxy, oxo (═O), alkoxycarbonyl, alkylcarbonyl orarylcarbonyl; and n is 0 or an integer from 1 to 4;

-   e) a group of formula (IIc) or (IId):

wherein R^(d), R′^(d) and R^(e) represent, the same or different andindependently from each other, a hydrogen atom or a straight or branchedC₁-C₆ alkyl optionally substituted by one or more groups selected fromhydroxy (—OH), aminocarbonyl (—CONH₂) or methylaminocarbonyl (—CONHCH₃);

-   provided that in formula (Ia), when R₁ is a group of formula (IIc)    and one of R^(d) or R′^(d) is a hydrogen atom whilst the other of    R^(d) or R′^(d) is ethyl or n-butyl, then R is other than —COR^(a)    with R^(a) as 3-bromophenyl, benzyl, 4-tert-butylphenyl,    4-tert-butylphenylmethyl, 4-fluorophenylmethyl, cyclopropyl or    2-naphthylmethyl;    or a pharmaceutically acceptable salt thereof.

Likewise, it is a further object of the present invention a library oftwo or more compounds of formula (Ib)

wherein

-   R is a group —COR^(a), —CONHR^(a) or —CONR^(a)R^(b) wherein R^(a)    and R^(b) are, each independently, hydrogen or an optionally    substituted group selected from straight or branched C₁-C₆ alkyl,    C₃-C₆ cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl    or; together with the nitrogen atom to which they are bonded, R^(a)    and R^(b) may form an optionally substituted 5 or 6 membered    heterocycle optionally containing one additional heteroatom or    heteroatomic group selected among N, NH, O or S;-   R₁ is selected from the group consisting of:-   a) straight or branched C₃-C₄ alkyl;-   b) cycloalkyl, cycloalkyl-alkyl or alkyl-cycloalkyl wherein the    cycloalkyl moiety comprises any C₃-C₆ cycloalkyl group and wherein    the alkyl moiety comprises any straight or branched C₁-C₄ alkyl    group:-   c) 3-methylthienyl-2-yl; 2-thienyl; phenyl; 2,6-difluorophenyl;    4-(aminosulfonyl)phenyl; 4-(dimethylaminomethyl)phenyl;    4-(4-methylpiperazinyl)methylphenyl;-   d) a group of formula (IIa) or (IIb):

wherein, in formula (IIa), the cycle represents a 5 to 7 memberedheterocyclic ring wherein X, directly linked to the rest of themolecule, represents a carbon or nitrogen atom; Y is a carbon, nitrogen,oxygen or sulfur atom or it is an NH group, provided that at least oneof X and Y is other than a carbon atom; R^(c) is, independently fromeach other and in any one of the free positions of the heterocyclic ringof formula (IIa), a halogen atom or hydroxy group or it is an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl, C₃-C₆cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, amino,aminocarbonyl, carboxy, oxo (═O), alkoxycarbonyl, alkylcarbonyl orarylcarbonyl; and n is 0 or an integer from 1 to 4;

-   e) a group of formula (IIc) or (IId):

wherein R^(d), R′^(d) and R^(e) represent, the same or different andindependently from each other, a hydrogen atom or a straight or branchedC₁-C₆ alkyl optionally substituted by one or more groups selected fromhydroxy (—OH), aminocarbonyl (—CONH₂) or methylaminocarbonyl (—CONHCH₃);or a pharmaceutically acceptable salt thereof.

For a general reference to the above libraries of compounds of formula(I) see the experimental section.

From all of the above, it is clear to the skilled person that once alibrary of pyrrolo-pyrazole derivatives is thus prepared, for instanceconsisting of a few hundreds or even a few thousands of compounds offormula (Ia) or (Ib), the said library can be very advantageously usedfor screening towards given kinases, as formerly reported.

See, for a general reference to libraries of compounds and uses thereofas tools for screening biological activities, J. Med. Chem. 1999, 42,2373-2382; and Bioorg. Med. Chem. Lett. 10 (2000), 223-226.

Pharmacology

The compounds of formula (I) are active as protein kinase inhibitors andare therefore useful, for instance, to restrict the unregulatedproliferation of tumor cells.

In therapy, they may be used in the treatment of various tumors, such asthose formerly reported, as well as in the treatment of other cellproliferative disorders such as psoriasis, vascular smooth cellproliferation associated with atherosclerosis and post-surgical stenosisand restenosis and in the treatment of Alzheimer's disease.

The inhibiting activity of putative Cdk/Cyclin inhibitors and thepotency of selected compounds was determined through a method of assaybased on the use of the SPA technology (Amersham Pharmacia Biotech).

The assay consists of the transfer of radioactivity labelled phosphatemoiety by the kinase to a biotinylated substrate. The resulting33P-labelled biotinylated product is allowed to bind tostreptavidin-coated SPA beads (biotin capacity 130 pmol/mg), and lightemitted was measured in a scintillation counter.

Inhibition Assay of Cdk2/Cyclin A Activity

Kinase reaction: 4 μM in house biotinylated histone H1 (Sigma #H-5505)substrate, 10 μM ATP (0.1 microCi P³³γ-ATP), 4.2 ng Cdk2/Cyclin Acomplex, inhibitor in a final volume of 30 μl buffer (TRIS HCl 10 mM pH7.5, MgCl₂ 10 mM, DTT 7.5 mM+0.2 mg/ml BSA) were added to each well of a96 U bottom. After 30 min at r.t. incubation, reaction was stopped by100 μl PBS+32 mM EDTA+0.1% Triton X-100+500 μM ATP, containing 1 mg SPAbeads. Then a volume of 110 μl is transferred to Optiplate.

After 20 min. incubation for substrate capture, 100 μl 5M CsCl wereadded to allow statification of beads to the top of the plate and letstand 4 hours before radioactivity counting in the Top-Count instrument

IC50 determination: inhibitors were tested at different concentrationsranging from 0.0015 to 10 μM. Experimental data were analyzed by thecomputer program GraphPad Prizm using the four parameter logisticequation:y=bottom+(top−bottom)/(1+10^((log IC50−x)*slope))where x is the logarithm of the inhibitor concentration, y is theresponse; y starts at bottom and goes to top with a sigmoid shape.Ki Calculation:

Experimental method: Reaction was carried out in buffer (10 mM Tris, pH7.5, 10 mM MgCl₂, 0.2 mg/ml BSA, 7.5 mM DTT) containing 3.7 nM enzyme,histone and ATP (constant ratio of cold/labeled ATP 1/3000). Reactionwas stopped with EDTA and the substrate captured on phosphomembrane(Multiscreen 96 well plates from Millipore). After extensive washing,the multiscreen plates are read on a top counter. Control (time zero)for each ATP and histone concentrations was measured.

Experimental design: Reaction velocities are measured at different fourATP, substrate (histone) and inhibitor concentrations. An 80-pointconcentration matrix was designed around the respective ATP andsubstrate Km values, and the inhibitor IC50 values (0.3, 1, 3, 9 foldthe Km or IC50 values). A preliminary time course experiment in theabsence of inhibitor and at the different ATP and substrateconcentrations allow the selection of a single endpoint time (10 min) inthe linear range of the reaction for the Ki determination experiment.

Kinetic parameter estimates: Kinetic parameters were estimated bysimultaneous nonlinear least-square regression using [Eq. 1](competitive inhibitor respect to ATP, random mechanism) using thecomplete data set (80 points):

$\begin{matrix}{v = \frac{{Vm} \cdot A \cdot B}{\begin{matrix}{{\alpha \cdot {Ka} \cdot {Kb}} + {\alpha \cdot {Ka} \cdot B} + {a \cdot {Kb} \cdot A} +} \\{{A \cdot B} + {\alpha \cdot \frac{Ka}{Ki} \cdot I \cdot \left( {{Kb} + \frac{B}{\beta}} \right)}}\end{matrix}}} & \left\lbrack {{Eq}.\mspace{14mu} 1} \right\rbrack\end{matrix}$where A=[ATP], B=[Substrate], I=[inhibitor], Vm=maximum velocity, Ka,Kb, Ki the dissociation constants of ATP, substrate and inhibitorrespectively. α and β the cooperativity factor between substrate and ATPbinding and substrate and inhibitor binding respectively.

In addition the selected compounds have been characterized on a panel ofser/threo kinases strictly related to cell cycle (Cdk2/Cyclin E,Cdk1/cyclin B1, Cdk5/p25, Cdk4/Cyclin D1), and also for specificity onMAPK, PKA, EGFR, IGF1-R, Aurora-2 and Akt.

Inhibition Assay of Cdk/Cyclin E Activity

Kinase reaction: 10 μM in house biotinylated histone H1 (Sigma #H-5505)substrate, 30 μM ATP (0.3 microCi P³³γ-ATP), 4 ng GST-Cdk2/Cyclin Ecomplex, inhibitor in a final volume of 30 μl buffer (TRIS HCl 10 mM pH7.5, MgCl₂ 10 mM, DTT 7.5 mM+0.2 mg/ml BSA) were added to each well of a96 U bottom. After 60 min at r.t. incubation, reaction was stopped by100 μl PBS+32 mM EDTA+0.1% Triton X-100+500 μM ATP, containing 1 mg SPAbeads. Then a volume of 110 μl is transferred to Optiplate.

After 20 min. incubation for substrate capture, 100 μl 5M CsCl wereadded to allow statification of beads to the top of the plate and letstand 4 hours before radioactivity counting in the Top-Count instrument

IC50 determination: see above

Inhibition Assay of Cdk1/Cyclin B1 Activity

Kinase reaction: 4 μM in house biotinylated histone H1 (Sigma #H-5505)substrate, 20 μM ATP (0.2 microCi P³³γ-ATP), 3 ng Cdk1/Cyclin B complex,inhibitor in a final volume of 30 μl buffer (TRIS HCl 10 mM pH 7.5,MgCl₂ 10 mM, DTT 7.5 mM+0.2 mg/ml BSA) were added to each well of a 96 Ubottom. After 20 min at r.t. incubation, reaction was stopped by 100 μlPBS+32 mM EDTA+0.1% Triton X-100+500 μM ATP, containing 1 mg SPA beads.Then a volume of 110 μl is transferred to Optiplate.

After 20 min. incubation for substrate capture, 100 μl 5M CsCl wereadded to allow statification of beads to the top of the Optiplate andlet stand 4 hours before radioactivity counting in the Top-Countinstrument.

IC50 determination: see above

Inhibition Assay of Cdk5/p25 Activity

The inhibition assay of Cdk5/p25 activity was performed according to thefollowing protocol.

Kinase reaction: 10 μM biotinylated histone H1 (Sigma #H-5505)substrate, 30 μM ATP (0.3 microCi P³³γ-ATP), 15 ng CDK5/p25 complex,inhibitor in a final volume of 30 μl buffer (TRIS HCl 10 mM pH 7.5,MgCl₂ 10 mM, DTT 7.5 mM+0.2 mg/ml BSA) were added to each well of a 96 Ubottom. After 30 min at r.t. incubation, reaction was stopped by 100 μlPBS+32 mM EDTA+0.1% Triton X-100+500 μM ATP, containing 1 mg SPA beads.Then a volume of 110 μl is transferred to Optiplate.

After 20 min. incubation for substrate capture, 100 μl 5M CsCl wereadded to allow statification of beads to the top of the plate and letstand 4 hours before radioactivity counting in the Top-Count instrument.

IC50 determination: see above

Inhibition Assay of Cdk4/Cyclin D1 Activity

Kinase reaction: 0.4 uM μM mouse GST-Rb (769-921) (#sc-4112 from SantaCruz) substrate, 10 μM ATP (0.5 μCi P³³γ-ATP), 100 ng of baculovirusexpressed GST-Cdk4/Cyclin D1, suitable concentrations of inhibitor in afinal volume of 50 μl buffer (TRIS HCl 10 mM pH 7.5, MgCl₂ 10 mM, 7.5 mMDTT+0.2 mg/ml BSA) were added to each well of a 96 U bottom well plate.After 40 min at 37° C. incubation, reaction was stopped by 20 μl EDTA120 mM.

Capture: 60 μl were transferred from each well to MultiScreen plate, toallow substrate binding to phosphocellulose filter. Plates were thenwashed 3 times with 150 μl/well PBS Ca⁺⁺/Mg⁺⁺ free and filtered byMultiScreen filtration system.

Detection: filters were allowed to dry at 37° C., then 100 μl/wellscintillant were added and ³³P labeled Rb fragment was detected byradioactivity counting in the Top-Count instrument.

IC50 determination: see above

Inhibition Assay of MAPK Activity

Kinase reaction: 10 μM in house biotinylated MBP (Sigma #M-1891)substrate, 15 μM ATP (0.15 microCi P³³γ-ATP), 30 ng GST-MAPK (UpstateBiotechnology #14-173), inhibitor in a final volume of 30 μl buffer(TRIS HCl 10 mM pH 7.5, MgCl₂ 10 mM, DTT 7.5 mM+0.2 mg/ml BSA) wereadded to each well of a 96 U bottom. After 30 min at r.t. incubation,reaction was stopped by 100 μl PBS+32 mM EDTA+0.1% Triton X-100+500 μMATP, containing 1 mg SPA beads. Then a volume of 110 μl is transferredto Optiplate.

After 20 min. incubation for substrate capture, 100 μl 5M CsCl wereadded to allow statification of beads to the top of the Optiplate andlet stand 4 hours before radioactivity counting in the Top-Countinstrument.

IC50 determination: see above

Inhibition Assay of PKA Activity

Kinase reaction: 10 μM in house biotinylated histone H1 (Sigma #H-5505)substrate, 10 μM ATP (0.2 microM P³³γ-ATP), 0.45 U PKA (Sigma #2645),inhibitor in a final volume of 30 μl buffer (TRIS HCl 10 mM pH 7.5,MgCl₂ 10 mM, DTT 7.5 mM+0.2 mg/ml BSA) were added to each well of a 96 Ubottom. After 90 min at r.t. incubation, reaction was stopped by 100 μlPBS+32 mM EDTA+0.1% Triton X-100+500 μM ATP, containing 1 mg SPA beads.Then a volume of 110 μl is transferred to Optiplate.

After 20 min. incubation for substrate capture, 100 μl 5M CsCl wereadded to allow statification of beads to the top of the Optiplate andlet stand 4 hours before radioactivity counting in the Top-Countinstrument.

IC50 determination: see above

Inhibition Assay of EGFR Activity

Kinase reaction: 10 μM in house biotinylated MBP (Sigma #M-1891)substrate, 2 μM ATP (0.04 microCi P³³γ-ATP), 36 ng insect cell expressedGST-EGFR, inhibitor in a final volume of 30 μl buffer (Hepes 50 mM pH7.5, MgCl₂ 3 mM, MnCl₂ 3 mM, DTT 1 mM, NaVO₃ 3 μM+0.2 mg/ml BSA) wereadded to each well of a 96 U bottom. After 20 min at r.t. incubation,reaction was stopped by 100 μl PBS+32 mM EDTA+0.1% Triton X-100+500 μMATP, containing 1 mg SPA beads. Then a volume of 110 μl is transferredto Optiplate.

After 20 min. incubation for substrate capture, 100 μl 5M CsCl wereadded to allow statification of beads to the top of the Optiplate andlet stand 4 hours before radioactivity counting in the Top-Countinstrument.

IC50 determination: see above

Inhibition Assay of IGF1-R Activity

The inhibition assay of IGF1-R activity was performed according to thefollowing protocol.

Kinase reaction: 10 μM biotinylated MBP (Sigma cat. #M-1891) substrate,0-20 μM inhibitor, 6 μM ATP, 1 microCi ³³P-ATP, and 22.5 ng GST-IGF1-R(pre-incubated for 30 min at room temperature with cold 60 μM cold ATP)in a final volume of 30 μl buffer (50 mM HEPES pH 7.9, 3 mM MnCl₂, 1 mMDTT, 3 μM NaVO₃) were added to each well of a 96 U bottom well plate.After incubation for 35 min at room temperature, the reaction wasstopped by addition of 100 μl PBS buffer containing 32 mM EDTA, 500 μMcold ATP, 0.1% Triton X100 and 10 mg/ml streptavidin coated SPA beads.After 20 min incubation, 110 μL of suspension were withdrawn andtransferred into 96-well OPTIPLATEs containing 100 μl of 5M CsCl. After4 hours, the plates were read for 2 min in a Packard TOP-Countradioactivity reader.

Inhibition Assay of Aurora-2 Activity

Kinase reaction: 8 μM biotinylated peptide (4 repeats of LRRWSLG), 10 μMATP (0.5 uCi P³³γ-ATP), 15 ng Aurora2, inhibitor in a final volume of 30μl buffer (HEPES 50 mM pH 7.0, MgCl₂ 10 mM, 1 mM DTT, 0.2 mg/ml BSA, 3μM orthovanadate) were added to each well of a 96 U bottom well plate.After 30 minutes at room temperature incubation, reaction was stoppedand biotinylated peptide captured by adding 100 μl of bead suspension.

Stratification. 100 μl of CsCl2 5 M were added to each well and letstand 4 hour before radioactivity was counted in the Top-Countinstrument.

IC50 determination: see above

Inhibition Assay of Cdc7/dbf4 Activity

The inhibition assay of Cdc7/dbf4 activity was performed according tothe following protocol.

The Biotin-MCM2 substrate is trans-phosphorylated by the Cdc7/Dbf4complex in the presence of ATP traced with γ³³-ATP. The phosphorylatedBiotin-MCM2 substrate is then captured by Streptavidin-coated SPA beadsand the extent of phosphorylation evaluated by β counting.

The inhibition assay of Cdc7/dbf4 activity was performed in 96 wellsplate according to the following protocol.

To each well of the plate were added:

-   -   10 μl substrate (biotinylated MCM2, 6 μM final concentration)    -   10 μl enzyme (Cdc7/Dbf4, 12.5 nM final concentration)    -   10 μl test compound (12 increasing concentrations in the nM to        μM range to generate a dose-response curve)    -   10 μl of a mixture of cold ATP (10 μM final concentration) and        radioactive ATP (1/2500 molar ratio with cold ATP) was then used        to start the reaction which was allowed to take place at 37° C.

Substrate, enzyme and ATP were diluted in 50 mM HEPES pH 7.9 containing15 mM MgCl₂, 2 mM DTT, 3 μM NaVO₃, 2 mM glycerophosphate and 0.2 mg/mlBSA. The solvent for test compounds also contained 10% DMSO.

After incubation for 20 minutes, the reaction was stopped by adding toeach well 100 μl of PBS pH 7.4 containing 50 mM EDTA, 1 mM cold ATP,0.1% Triton X100 and 10 mg/ml streptavidin coated SPA beads.

After 15 minutes of incubation at room temperature to allow thebiotinylated MCM2-streptavidin SPA beads interaction to occur, beadswere trapped in a 96 wells filter plate (Unifilter® CF/B™) using aPackard Cell Harvester (Filtermate), washed with distilled water andthen counted using a Top Count (Packard).

Counts were blank-subtracted and then the experimental data (each pointin triplicate) were analyzed for IC50 determination using a non-linearregression analysis (Sigma Plot). Given the above inhibition assays, thecompounds of formula (I) of the invention resulted to possess aremarkable cdk inhibitory activity. See, as an example, the followingexperimental data (IC₅₀) of two representative compounds of theinvention of formula (Ia) and (Ib) being tested against Cdk2/Cyclin A:

-   Compound 1:    N-[5-(2,2-dimethylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-4-fluorobenzamide    (IC₅₀ 0.030 μM); and-   Compound 2:    N-[5-(2,2-dimethylpropanoyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-6-spirocyclopropan-3-yl]-4-fluorobenzamide    (IC₅₀ 0.025 μM).

Surprisingly, the said inhibitory activity resulted to be markedlysuperior that that of a very close compound of the prior art WO02/12242, herewith referred to as Reference compound (see compound 1143,bottom of page 76; and example 19, compound bridging pages 242-3 of WO02/12242), used for comparative purposes and tested against Cdk2/CyclinA, as formerly reported:

-   Reference Compound:    N-[5-acetyl-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazol-3-yl]-(3-bromo)benzamide    (IC₅₀ 1.7 μM)

So far, the novel compounds of the invention are unexpectedly endowedwith a cdk inhibitory activity significantly higher than that of thestructurally closest prior art compounds of WO 02/12242 and are thusparticularly advantageous, in therapy, against proliferative disordersassociated with an altered cell cycle dependent kinase activity.

The compounds of the present invention can be administered either assingle agents or, alternatively, in combination with known anticancertreatments such as radiation therapy or chemotherapy regimen incombination with cytostatic or cytotoxic agents, antibiotic-type agents,alkylating agents, antimetabolite agents, hormonal agents, immunologicalagents, interferon-type agents, cyclooxygenase inhibitors (e.g. COX-2inhibitors), matrixmetalloprotease inhibitors, telomerase inhibitors,tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HERagents, anti-EGFR agents, anti-angiogenesis agents (e.g. angiogenesisinhibitors), farnesyl transferase inhibitors, ras-raf signaltransduction pathway inhibitors, cell cycle inhibitors, other cdksinhibitors, tubulin binding agents, topoisomerase I inhibitors,topoisomerase II inhibitors, and the like.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent within the approved dosagerange.

Compounds of formula (I) may be used sequentially with known anticanceragents when a combination formulation is inappropriate.

The compounds of formula (I) of the present invention, suitable foradministration to a mammal, e.g., to humans, can be administered by theusual routes and the dosage level depends upon the age, weight,conditions of the patient and administration route.

For example, a suitable dosage adopted for oral administration of acompound of formula (I) may range from about 10 to about 500 mg perdose, from 1 to 5 times daily. The compounds of the invention can beadministered in a variety of dosage forms, e.g., orally, in the formtablets, capsules, sugar or film coated tablets, liquid solutions orsuspensions; rectally in the form suppositories; parenterally, e.g.,intramuscularly, or through intravenous and/or intrathecal and/orintraspinal injection or infusion.

The present invention also includes pharmaceutical compositionscomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof in association with a pharmaceutically acceptableexcipient, which may be a carrier or a diluent.

The pharmaceutical compositions containing the compounds of theinvention are usually prepared following conventional methods and areadministered in a suitable pharmaceutical form. For example, the solidoral forms may contain, together with the active compound, diluents,e.g., lactose, dextrose saccharose, sucrose, cellulose, corn starch orpotato starch; lubricants, e.g., silica, talc, stearic acid, magnesiumor calcium stearate, and/or polyethylene glycols; binding agents, e.g.,starches, arabic gum, gelatine methylcellulose, carboxymethylcelluloseor polyvinyl pyrrolidone; disintegrating agents, e.g., starch, alginicacid, alginates or sodium starch glycolate; effervescing mixtures;dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates,laurylsulphates; and, in general, non-toxic and pharmacologicallyinactive substances used in pharmaceutical formulations. Thesepharmaceutical preparations may be manufactured in known manner, forexample, by means of mixing, granulating, tabletting, sugar-coating, orfilm-coating processes.

The liquid dispersions for oral administration may be, e.g., syrups,emulsions and suspensions. As an example, the syrups may contain, ascarrier, saccharose or saccharose with glycerine and/or mannitol andsorbitol.

The suspensions and the emulsions may contain, as examples of carriers,natural gum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose, or polyvinyl alcohol. The suspension orsolutions for intramuscular injections may contain, together with theactive compound, a pharmaceutically acceptable carrier, e.g., sterilewater, olive oil, ethyl oleate, glycols, e.g., propylene glycol and, ifdesired, a suitable amount of lidocaine hydrochloride.

The solutions for intravenous injections or infusions may contain, as acarrier, sterile water or preferably they may be in the form of sterile,aqueous, isotonic, saline solutions or they may contain propylene glycolas a carrier.

The suppositories may contain, together with the active compound, apharmaceutically acceptable carrier, e.g., cocoa butter, polyethyleneglycol, a polyoxyethylene sorbitan fatty acid ester surfactant orlecithin.

With the aim of better illustrating the present invention, withoutposing any limitation to it, the following examples are now given.

General Methods

Before taking into consideration the synthetic preparation of thespecific compounds of formula (I) of the invention, for instance asreported in the following examples, attention should be given to thefact that some compounds are herewith listed and indicated according totheir chemical name whilst others, most of them, have been convenientlyand unambiguously identified through a coding system, together withtheir ¹H-NMR data (see following tables III, IV and V) and HPLC/Massdata (see following table VI).

Each code, in particular, identifies a single specific compound offormula (Ia) or (Ib) and consists of three units A-M-B.

A represents any substituent R [see formula (Ia) or (Ib)] and isattached to the rest of the molecule through the —NH-group; eachspecific A group is represented and consecutively numbered in thefollowing table I.

Likewise, B represents any substituent R₁ [see formula (Ia) or (Ib)] andis attached to the rest of the molecule through the carbonyl (CO) group;each specific B group is represented and consecutively numbered in thefollowing table II.

M refers to the central core of the divalent moiety which is substitutedby groups A and B; in particular, M may vary from M1 or M2 as per theformulae below, each identifying the central core of a compound havingformula (Ia) or (Ib), respectively:

For ease of reference, all of the A and B groups of tables I and II havebeen identified with the proper chemical formula also indicating thepoint of attachment with the rest of the molecule M.

Therefore, just as an example, the compound A06-M1-B01 of table IIIrepresents the compound of formula (Ia) having the central M1 core,being substituted by the group A06 and by the group B01, in thepositions indicated by the arrows; likewise, the compound A04-M2-B08 oftable V represents the compound of formula (Ib) having the central M2core, being substituted by the group A04 and by the group B08, in thepositions indicated by the arrows:

TABLE I

A06-M1-B01

A04-M2-B08 A01

A02

A03

A04

A05

A06

A07

A08

A09

A10

A11

A12

A13

A14

A15

A16

A17

A18

A19

A20

A21

A22

A23

A24

A25

A26

A27

A28

A29

A30

A31

A32

A33

A34

A35

A36

A37

A38

A39

A40

A41

A42

A43

A44

A45

A46

A47

A48

A49

A50

A51

A52

A53

A54

A55

TABLE II B01

B02

B03

B04

B05

B06

B07

B08

B09

B10

B11

B12

B13

B14

B15

B16

B17

B18

B19

B20

B21

B22

B23

B24

B25

B26

B27

B28

B29

B30

B31

B32

B33

B34

B35

B36

B37

B38

B39

B40

B41

B42

B43

B44

B45

B46

B47

B48

B49

B50

B51

B52

B53

B54

B55

EXAMPLE 1 N-(2-cyanoethyl)-2-methylalanine

50 g (0.48 mol) of 2-methylalanine were added to a cooled solution(water/ice) of NaOH (19.6 g) in water (100 ml). Once the solution hadturned clear, 34 ml (0.50 mol) of acrylonitrile were dropped on cooling.The mixture was left overnight. After 18 hours, 28 ml of acetic acidwere added on cooling (water/ice); a white solid precipitated; 200 ml of95% ethanol were dropped in the flask, stirring was continued for 1hour, then the mixture was allowed to stand in a fridge for 2-3 hours.After filtration, the solid was collected and dried in an oven at 80° C.The filtrates were evaporated and taken up with ethanol (160 ml). Oncooling a further amount of product was obtained, which was filtered anddried. 72 g of the title compound were obtained from the firstfiltration. Total yield: 95%.

ESI MSS: m/z 157 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 7.47 (s, 1H), 2.70 (t, 2H), 2.48 (t, 2H),1.18 (s, 6H).

By working in an analogous manner the following compound was prepared:

1-[(2-Cyanoethyl)amino]cyclopropanecarboxylic acid

EI MS: m/z 154 (M), 136 (M−H₂O), 114 (M−CH2CN), 68 (100%, cyclopr=C═O);

¹H NMR (400 MHz, DMSO-d₆): δ 7.47 (s, 1H), 2.86 (t, 2H, J=6.6 Hz), 2.48(t, 2H, J=6.6 Hz), 1.09 (dd, 2H, J=6.9 Hz, J=4.1 Hz), 0.86 (dd, 2H,J=6.9 Hz, J=4.1 Hz).

EXAMPLE 2 N-(tert-butoxycarbonyl)-N-(2-cyanoethyl)-2-methylalanine

44.5 g (0.285 mol) of N-(2-cyanoethyl)-2-methylalanine and 51.7 g oftetramethylammonium hydroxide pentahydrate were dissolved inacetonitrile (2 l) at 40° C. and when a clear solution was obtained, 112g of Boc₂O were added. The mixture was left for 24 hours at 40° C. Theday after, further 20 g of Boc₂O were added while maintaining thetemperature of 40° C. Every 8-12 hours 20 g of Boc₂O were added up to atotal of 192 g. After 4 days the solvent was evaporated, the residuetaken up with water (1000 ml) and washed twice with ethyl ether (500ml). The aqueous fraction was brought to pH 3-4 with citric acid andextracted with ethyl acetate, washed with water (200 ml) andconcentrated. 52 g of the title compound were obtained. (yield: 72%).

ESI MS: m/z 274 (M+NH4);

¹H NMR (400 MHz, DMSO-d₆): δ 3.52 (t, 2H, J=6.8 Hz)), 2.68 (t, 2H, J=6.8Hz), 1.18-1.38 (m, 15H).

By working in an analogous manner the following compound was prepared:

1-[(tert-Butoxycarbonyl)(2-cyanoethyl)amino]cyclopropanecarboxylic acid

ESI MS: m/z 272 (M+NH4), 255 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 12.55 (bs, 1H), 3.33 (m, 2H), 2.71 (m, 2H),0.97-1.63 (m, 13H).

EXAMPLE 3 MethylN-(tert-butoxycarbonyl)-N-(2-cyanoethyl)-2-methylalaninate

62 g (0.23 mol) ofN-(tert-butoxycarbonyl)-N-(2-cyanoethyl)-2-methylalanine were dissolvedin 350 ml of DMF and 50 g of KHCO₃ were added. Few minutes after, 30 mlof methyl iodide (MeI) were dropped and the mixture was stirred at roomtemperature for 6 hours. Then a further 15 ml of MeI were added. Themixture was left at room temperature overnight. After dilution with 1.5l of water, the solution was extracted with ethyl acetate (3 times). Theorganic phases were washed with a small amount of water, dried oversodium sulfate, evaporated and dried at the mechanical pump. 60.5 g(97%) of methylN-(tert-butoxycarbonyl)-N-(2-cyanoethyl)-2-methylalaninate were thusobtained.

ESI MS: m/z 288 (M+NH4);

¹H NMR (400 MHz, DMSO-d₆): δ 3.55 (m, 5H), 2.70 (t, 2H, J=6.7 Hz)), 1.40(s, 6H), 1.36 (s, 9H).

By working in an analogous manner the following compound was prepared:

Methyl1-[(tert-butoxycarbonyl)(2-cyanoethyl)amino]cyclopropanecarboxylate

ESI MS: m/z 286 (M+NH4);

¹H NMR (400 MHz, DMSO-d₆): δ 3.61 (s, 3H), 3.42 (t, 2H, J=6.7 Hz), 2.71(m, 2H), 1.07-1.62 (m, 13H).

EXAMPLE 4 tert-Butyl4-cyano-3-hydroxy-2,2-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxylate

45 g of methylN-(tert-butoxycarbonyl)-N-(2-cyanoethyl)-2-methylalaninate weredissolved in dioxane (240 ml) under nitrogen and 7.9 g of sodium hydridewere added. The mixture was refluxed for 6 hours (120° C. internaltemperature), and then left to stand overnight at room temperature (TLC:CH₂Cl₂/EtOH 90/10). The solvent was evaporated, water was added (1000ml) and the mixture was brought to pH 3-4 with citric acid. The aqueouslayer was extracted 4 times with ethyl acetate, the extracts washed witha limited amount of water and evaporated. Then the residue was taken upwith hexane, evaporated and crystallized from hexane. 33.1 g oftert-butyl4-cyano-3-hydroxy-2,2-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxylate werethus obtained (yield: 85%).

ESI MS: m/z 237 (M−H—);

¹H NMR (400 MHz, DMSO-d₆): δ 4.06-4.10 (2s, 2H, conformers), 1.48 (s,6H), 1.47 (s, 9H).

By working in an analogous manner the following compound was prepared:

tert-Butyl 6-cyano-7-oxo-4-azaspiro[2.4]heptane-4-carboxylate

ESI MS: m/z 235 (M−H—);

¹H NMR (400 MHz, DMSO-d₆): δ 4.63 (t, 1H, J=9.8 Hz), 4.24 (t, 1H, J=10.2Hz), 3.74 (t, 1H, J=10.2 Hz), 1.67-2.16 (m, 2H), 1.34-1.41 (s, 9H),0.93-1.20 (m, 2H).

EXAMPLE 5 tert-Butyl3-amino-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate

32 g of tert-Butyl4-cyano-3-hydroxy-2,2-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxylate(0.134 mol) were added to 430 ml of absolute ethanol. To this solution,9 ml (0.18 mol) of hydrazine hydrate were added, followed by 12 ml ofglacial AcOH (1.5 eq); The mixture was stirred at 60° C. for 48 hours,the ethanol was removed, the residue was taken up with 400 ml of sodiumhydrogencarbonate solution, and extracted several times with ethylacetate up to total extraction of the desired product. The organicphases were dried and evaporated. After purification by flashchromatography (eluent: CHCl₃/EtOH 97/3) and trituration with a mixtureof hexane/ethyl acetate 9/1, 25 g of title compound were obtained. Totalyield 30.5 g (yield: 88%)

ESI MS: m/z 253 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 4.06-4.10 (2s, 2H, conformers), 1.48 (2s,6H, conformers), 1.47 (2s, 9H, conformers).

By working in an analogous manner the following compound was prepared:

tert-Butyl-3-amino-2,6-dihydropyrrolo[3,4-c]pyrazole-6-spirocyclopropane-5(4H)-carboxylate

ESI MS: m/z 251 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 11.12 (bs, 1H), 5.13 (bs, 2H), 4.16-4.33(m, 2H), 1.57-1.91 (m, 2H), 1.38 (s, 9H), 0.65-0.83 (m, 2H).

EXAMPLE 6 5-tert-Butyl 2-ethyl3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate and5-tert-butyl 1-ethyl3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate

15 g of tert-Butyl3-amino-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate(59.4 mmol) were dissolved in anhydrous THF (150 ml) and treated, at 0°C. under Ar atmosphere, first with N,N-diisopropylethylamine (50 ml) andthen with ClCO₂Et (4.65 ml, 1 eq.) dropwise. 90 minutes later, thesolvent was diluted with EtOAc (1 l), washed with water and then withbrine, dried over sodium sulfate and evaporated. The crude product waspurified by flash chromatography (hexane/EtOAc 2/8) to afford 7.3 g of5-tert-butyl 2-ethyl3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate asthe major compound in 38% yield, together with 5.7 g of 5-tert-butyl1-ethyl3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylatein 30% yield.

5-tert-Butyl 2-ethyl3-amino-6,6-dimethylpyrrolo[3,4-e]pyrazole-2,5(4H,6H)-dicarboxylate

ESI MS: m/z 325 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 4.35 (q, 2H), 4.10 (2s, 2H, conformers),1.50-1.51 (m, 6H), 1.41-1.43 (2s, 9H, conformers), 1.29 (t, 3H).

5-tert-Butyl 1-ethyl3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate

ESI MS: m/z 325 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 4.28 (q, 2H, J=7.1 Hz), 4.09-4.14 (2s, 2H,conformers), 1.66-1.67 (m, 6H), 1.41-1.44 (2s, 9H, conformers), 1.27 (t,3H, J=7.1 Hz).

By working in an analogous manner the following compounds were prepared:

5-tert-Butyl 2-ethyl3-amino-pyrrolo[3,4-c]pyrazole-6-spirocyclopropane-2,5(4H,6H)-dicarboxylate

ESI MS: m/z 323 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 4.30 (q, 2H, J=7.1 Hz), 4.27 (bs, 2H),1.65-2.01 (m, 2H), 1.38 (s, 9H) 1.27 (t, 3H, J=7.1 Hz), 0.82-0.96 (m,2H).

5-tert-Butyl 1-ethyl3-amino-4,6-dihydropyrrolo[3,4-c]pyrazole-6-spirocyclopropane-1,5-dicarboxylate

ESI MS: m/z 323 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 4.26 (bs, 2H), 4.21 (q, 2H, J=7.0 Hz),1.36-1.97 (m, 13H), 1.23 (t, 3H, J=7.0 Hz).

EXAMPLE 7 5-tert-Butyl 1-ethyl3-[(4-fluorobenzoyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate

5-tert-Butyl 1-ethyl3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate(2.0 g, 6.16 mmol) was dissolved in THF (40 ml), treated first withN,N-diisopropylethylamine (5.4 ml, 30.80 mmol) and then, at 0° C., with4-fluorobenzoyl chloride (800 μl, 6.77 mmol) dissolved in THF (8 ml)dropwise. The reaction mixture was stirred at room temperature for 5hours, concentrated and dissolved in DCM, washed with saturated sodiumhydrogencarbonate aqueous solution and with brine. The organic phase wasdried over sodium sulfate, evaporated and purified by flashchromatography (eluent: hexane/EtOAc 80/20) to afford 2.5 g of the titlecompound in 90% yield.

EST MS: m/z 447 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 11.47 (s, 1H), 8.04-8.17 (m, 2H), 7.25-7.37(m, 2H), 4.44-4.47 (2s, 2H, conformers), 4.43 (q, 2H, J=7.1 Hz),1.73-1.75 (2s, 6H, conformers), 1.43-1.46 (2s, 9H, conformers), 1.33 (t,3H, J=7.1 Hz).

By working in an analogous manner the following compounds were prepared.

5-tert-Butyl 2-ethyl3-[(4-fluorobenzoyl)amino]-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate

ESI MS: m/z 447 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 10.78 (s, 1H), 7.95-7.99 (m, 2H), 7.40-7.47(m, 2H), 4.51-4.49 (2s, 2H, conformers), 4.43 (q, 2H, J=7.1 Hz),1.59-1.60 (2s, 6H), 1.43-1.46 (2s, 9H, conformers), 1.34 (t, 3H, J=7.1Hz).

5-tert-Butyl 2-ethyl3-[(4-fluorobenzoyl)amino]-pyrrolo[3,4-c]pyrazole-6-spirocyclopropane-2,5(4H,6H)-dicarboxylate

ESI MS: m/z 445 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 10.81 (s, 1H), 7.95-8.06 (m, 2H), 7.39-7.49(m, 2H), 4.67 (bs, 2H), 4.41 (q, 2H, J=7.1 Hz), 1.80-2.10 (m, 2H), 1.41(s, 9H), 1.32 (t, 3H, J=7.1 Hz), 0.93-1.06 (m, 2H).

EXAMPLE 8 5-tert-Butyl 1-ethyl3-({[(3-fluorophenyl)amino]carbonyl}amino)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate

5-tert-Butyl 1-ethyl3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate(3.0 g, 9.24 mmol) was dissolved in anhydrous THF (50 ml), treated atroom temperature with 3-fluorophenyl-isocyanate (1.4 g, 10.21 mmol, 1.1eq) and stirred overnight. The following day the reaction mixture wasevaporated, taken up with DCM and washed with brine. The organic phasewas dried over sodium sulfate and evaporated to dryness. Purification byflash chromatography (CH₂Cl₂/MeOH 90/10) afforded 3.05 g (yield 71%) ofthe title compound.

ESI MS: m/z 462 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 9.74 (s, 1H), 9.05 (s, 1H), 7.44 (m, 1H),7.33 (m, 1H), 7.16 (m, 1H), 6.84 (m, 1H), 4.43 (m, 4H), 1.76 (2s, 6H),1.48 (2s, 9H, conformers), 1.36 (t, 3H, J=7.1 Hz).

EXAMPLE 9 5-tert-Butyl 1-ethyl3-[(piperidine-1-carbonyl)-amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate

To a solution of triphosgene (550 mg, 1.85 mmol, 0.4 eq) intetrahydrofuran (50 ml) was added, at −40° C., a solution of5-tert-butyl 1-ethyl3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate(1.5 g, 4.62 mmol) in tetrahydrofuran (50 ml) andN,N-diisopropylethylamine (1.8 ml, 2.2 eq). After 3 hours, a solution ofpiperidine (690 μl, 1.5 eq) and N,N-diisopropylethylamine (1.2 ml, 1.5eq) in tetrahydrofuran (25 ml) was added. The reaction was allowed toreach room temperature in 2 hours (TLC: EtOAc/hexane 90/10). Afterevaporation of the solvent the solid was dissolved in DCM and thesolution was washed with brine, the organic phase was dried over sodiumsulfate and concentrated. The solid was purified by flash chromatography(eluent: EtOAc/hexane 50/50). The solid was treated withdiisopropylether and filtered to afford 1.45 g of the title compound in72% yield.

ESI MS: m/z 436 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 9.36 (s, 1H), 4.46 (m, 4H), 3.40 (m, 4H),1.76 (2s, 6H), 1.54 (m, 6H), 1.44 (2s, 9H, conformers), 1.36 (t, 3H,J=7.1 Hz).

EXAMPLE 10 Ethyl3-[(4-fluorobenzoyl)amino]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-e]pyrazole-1(4H)-carboxylatehydrochloride

5-tert-Butyl 1-ethyl3-[(4-fluorobenzoyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate(2.5 g, 5.59 mmol) was dissolved in dioxane (50 ml) and treated with HCl4M in dioxane (28 ml, 20 eq). After 2 hours at 40° C. (TLC: CH₂Cl₂/MeOH90/10) the reaction mixture was concentrated and the residue was treatedwith diethyl ether, filtered to afford the title compound (2.09 g) as asolid in 98% yield.

ESI MS: m/z 347 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 11.28 (s, 1H), 8.06-8.11 (m, 2H), 7.28-7.34(m, 2H), 4.40 (q, 2H, J=7.1 Hz), 3.92 (s, 2H), 1.42 (s, 6H), 1.33 (t,3H, J=7.1 Hz).

By working in an analogous manner the following compounds were prepared:

Ethyl3-[(4-fluorobenzoyl)amino]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylatehydrochloride

ESI MS: m/z 347 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 10.92 (s, 1H), 9.89 (s, 1H), 8.02 (m, 2H),7.49 (m, 2H), 4.61 (s, 2H), 4.51 (q, 2H, J=7.1 Hz), 1.69 (s, 6H), 1.39(t, 3H, J=7.1 Hz).

Ethyl3-[(4-fluorobenzoyl)amino]-5,6-dihydropyrrolo[3,4-c]pyrazole-6-spirocyclopropane-2(4H)-carboxylatehydrochloride

ESI MS: m/z 345 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 10.87 (bs, 1H), 10.00 (bs, 2H), 7.93-8.04(m, 2H), 7.39-7.53 (m, 2H), 4.69 (bs, 2H), 4.41 (q, 2H, J=7.1 Hz), 1.68(dd, 2H, J=8.6 Hz, J=6.1 Hz), 1.41 (dd, 2H, J=8.6 Hz, J=6.1 Hz), 1.33(t, 3H, J=7.1 Hz).

EXAMPLE 11 Ethyl5-(2,2-dimethylpropanoyl)-3-[(4-fluorobenzoyl)amino]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-e]pyrazole-1(4H)-carboxylate

Ethyl3-[(4-fluorobenzoyl)amino]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylatehydrochloride (2.0 g, 5.77 mmol) in dichloromethane (70 ml) was treated,at 0° C., with N,N-diisopropylethylamine (1.6 ml, 9.2 mmol, 1.6 eq) andwith pivaloyl chloride (780 μL, 6.3 mmol, 1.1 eq). Gradually, thereaction was brought to room temperature and stirred overnight (TLC:CH₂Cl₂/EtOAc 90/10). The solution was washed with saturated sodiumhydrogencarbonate aqueous solution and brine. The organic phase wasdried over sodium sulfate, evaporated and purified by flashchromatography (eluent: CH₂Cl₂/EtOAc 90/10) to afford 2.03 g of thetitle compound in 82% yield.

ESI MS: m/z 431 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 11.51 (s, 1H), 8.05-8.14 (m, 2H), 7.23-7.37(m, 2H), 4.90 (s, 2H), 4.42 (q, 2H, J=7.1 Hz), 1.80 (s, 6H), 1.33 (t,3H, J=7.1 Hz), 1.22 (s, 9H).

By working in an analogous manner the following compound was prepared:

Ethyl 5-(2,2-dimethylpropanoyl)-3-[(4-fluorobenzoyl)amino]-5,6-dihydropyrrolo[3,4-c]pyrazole-6-spirocyclopropane-2(4H)-carboxylate

ESI MS: m/z 429 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 10.81 (bs, 1H), 7.96-8.04 (m, 2H),7.38-7.48 (m, 2H), 5.10 (bs, 2H), 4.42 (q, 2H, J=7.1 Hz), 2.33 (dd, 2H,J=6.8 Hz, J=4.2 Hz), 1.32 (t, 3H, J=7.1 Hz), 1.22 (s, 9H), 0.90 (dd, 2H,J=6.8 Hz, J=4.2 Hz).

EXAMPLE 12N-[5-(2,2-dimethylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-4-fluorobenzamide

Ethyl5-(2,2-dimethylpropanoyl)-3-[(4-fluorobenzoyl)amino]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate(2.0 g, 4.64 mmol) was dissolved in methanol (60 ml), treated with TEA(6.45 ml, 46.4 mmol, 10 eq) and stirred overnight at room temperature.(TLC: CH₂Cl₂/MeOH 95/5). After evaporation, the solid was treated withdiethyl ether/hexane and filtered to afford 1.43 g of the title compoundin 86% yield.

ESI MS: m/z 359 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 12.41 (bs, 1H), 10.91 (bs, 1H), 7.98-8.11(m, 2H), 7.20-7.44 (m, 2H), 4.66-4.92 (bs, 2H), 1.64 (s, 6H), 1.21 (s,9H).

By working in an analogous manner the following compounds were prepared:

N-[5-(2,2-dimethylpropanoyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-6-spirocyclopropan-3-yl]-4-fluorobenzamide

ESI MS: m/z 357 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 11.59-12.47 (bs, 1H), 10.94 (bs, 1H),8.02-8.11 (m, 2H), 7.27-7.37 (m, 2H), 4.99 (s, 2H), 2.25 (dd, 2H, J=6.5Hz, J=4.4 Hz), 1.20 (s, 9H), 0.79 (dd, 2H, J=6.5 Hz, J=4.4 Hz).

N-{6,6-dimethyl-5-[(2R)-tetrahydrofuran-2-ylcarbonyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-fluorobenzamide

ESI MS: m/z 373 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 12.49 (bs, 1H), 10.96 (bs, 1H), 8.09 (m,2H), 7.34 (m, 2H), 4.86 (m, 2H), 4.56 (t, 1H), 3.83 (m, 2H) 2.02 (m,2H), 1.86 (m, 2H), 1.68 (s, 6H).

α_(D) +27.7 (c=0.50, MeOH)

N-{6,6-dimethyl-5-[(2S)-tetrahydrofuran-2-ylcarbonyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-fluorobenzamide

ESI MS: m/z 373 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 12.49 (bs, 1H), 10.96 (bs, 1H), 8.09 (m,2H), 7.34 (m, 2H), 4.86 (m, 2H), 4.56 (t, 1H), 3.83 (m, 2H) 2.02 (m,2H), 1.86 (m, 2H), 1.68 (s, 6H).

α_(D) −25.9 (c=0.76, MeOH)

EXAMPLE 13 4-(1-Methyl-piperidin-4-yloxy)-benzoic acid methyl ester

To a solution of 1-methyl-piperidin-4-ol (6.8 g. 59 mmoles), PPh₃(triphenylphosphine, 15.5 g, 59 mmoles) and 4-hydroxy-benzoic acidmethyl ester (6 g, 39 mmoles) in THF (150 ml) at 0° C., diethylazodicarboxylate (9.5 ml, 59 mmoles) in THF (30 ml) was slowly added.The reaction mixture was allowed to warm to room temperature over aperiod of 24 hours. It was then evaporated and the residue redissolvedin 5% aqueous citric acid (700 ml). The solution was washed with ethylacetate (3×250 ml), made alkaline with concentrated NH₄OH (pH ˜8) andthen extracted with dichloromethane (3×250 ml). The combineddichloromethane extracts were washed with brine, dried and evaporated togive an oil which was purified by flash chromatography on silica gelusing dichloromethane-MeOH (90:10) as eluent, to give the title compoundas a yellow oil (7.4 g, 75%).

ESI MS: m/z 250 (MH+);

¹H NMR (400 MHz, DMSO-D6) δ ppm 1.7 (m, 2H) 2.0 (m, 2H) 2.2 (m, 5H) 2.7(m, 2H) 3.8 (s, 3H) 4.5 (m, 1H) 7.1 (d, J=9.0 Hz, 2H) 7.9 (d, J=9.0 Hz,2H).

EXAMPLE 14 4-(1-Methyl-piperidin-4-yloxy)-benzoic acid, hydrochloride

4-(1-Methyl-piperidin-4-yloxy)-benzoic acid methyl ester (7.3 g, 29mmoles) was dissolved in 6N aq HCl (220 ml). After heating at 85° C. for6 hours, the solvent was removed in vacuo. The residue was taken up withwater and evaporated twice and then taken up with acetone two moretimes. The solid obtained was finally triturated in acetone to give thehydrochloride salt as a white powder (6.4 g, 80% yield).

¹H NMR (400 MHz, DMSO-D6) δ ppm 2.0 (m, 4H) 2.8 (m, 3H) 3.3 (m, 4H) 4.7(m, 1H) 7.1 (m, 2H) 7.9 (m, 2H) 9.9 (d, J=20.4 Hz, 1H) 12.6 (s, 1H).

EXAMPLE 15 4-(4-Hydroxy-piperidin-1-yl)benzoic acid ethyl ester

A mixture of 4-fluoro-benzoic acid ethyl ester (1.68 g, 10 mmoles),piperidin-4-ol (1.12 g, 11 mmoles) and anhydrous potassium carbonate(1.38 g, 10 mmoles) in DMSO (10 ml) was heated at 120° C. for 6 hours.After cooling, the mixture was poured into water and ice (500 ml) andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried and evaporated. The residue was purified by flashchromatography on silica gel using hexane/EtOAc (10/30) as eluent togive the title compound as a white solid (1.6 g, 64%).

ESI MS: m/z 250 (MH+);

¹H NMR (400 MHz, DMSO-D6) δ ppm 1.3 (t, J=7.1 Hz, 3H) 1.4 (m, 2H) 1.8(m, 2H) 3.0 (m, 2H) 3.7 (m, 2H) 4.2 (q, J=7.1 Hz, 2H) 4.7 (d, J=4.3 Hz,1H) 6.9 (m, 2H) 7.7 (m, 2H).

EXAMPLE 16 4-(4-Fluoro-piperidin-1-yl)benzoic acid ethyl ester

To a solution of 4-(4-hydroxy-piperidin-1-yl)benzoic acid ethyl ester(1.25 g. 5 mmoles) in dry dichloromethane (30 ml) at room temperatureunder an inert atmosphere, it was slowly added DAST (0.97 g, 6 mmoles)in dichloromethane (5 ml). The reaction mixture was stirred at roomtemperature for 1 hour and then quenched with aqueous NaHCO₃. Theorganic layer was washed with brine, dried and evaporated. The residuewas purified by flash chromatography on silica gel using hexane/EtOAc(70/30) as eluent to give the title compound as a white solid (0.7 g,56%).

ESI MS: m/z 252 (MH+);

1H NMR (400 MHz, DMSO-D6) δ ppm 1.3 (t, J=7.1 Hz, 3H) 1.8 (m, 2H) 2.0(m, 2H) 3.3 (m, 2H) 3.6 (m, 2H) 4.2 (s, 2H) 4.8 (s, 1H) 7.0 (s, 2H) 7.8(s, 2H).

EXAMPLE 17 4-(4-Fluoro-piperidin-1-yl)benzoic acid

A mixture of 4-(4-fluoro-piperidin-1-yl)benzoic acid ethyl ester (0.7 g,2.7 mmoles) in ethanol (50 ml) and a solution of 2N sodium hydroxide (20ml) was stirred at room temperature for 24 hours. The ethanol was thenevaporated, the solution diluted with water (20 ml) and neutralized with2N HCl. The acid separated as a white solid which was washed with waterand dried under vacuum (0.52 g, 82%).

ESI MS: m/z 224 (MH+);

¹H NMR (400 MHz, DMSO-D6) δ ppm 1.8 (m, 2H) 2.0 (m, 2H) 3.3 (m, 2H) 3.5(m, 2H) 5.0 (s, 1H) 7.0 (s, 2H) 7.8 (s, 2H) 12.2 (s, 1H).

By working as described in any previous example, that is by using anyproper starting material and any suitable reactant according to theprocess previously disclosed, additional compounds of formula (Ia) and(Ib) were also prepared, as reported in the following table III. Forexplanatory notes concerning the coding system identifying each specificcompound of formula (Ia) and (Ib) see the “general method” at thebeginning of the experimental section.

TABLE III A02M1B01 ¹H NMR (400 MHz, DMSO-d₆): δ 12.45 (bs, 1H), 10.99(s, 1H), 7.84 (m, 2H), 7.52 (m, 1H), 7.40 (m, 1H), 4.86 (s, 2H), 1.65(s, 6H), 1.21 (s, 9H). A03M1B01 ¹H NMR (400 MHz, DMSO-d₆): δ 12.46 (bs,1H), 11.01 (s, 1H), 8.05 (m, 1H), 7.88 (m, 1H), 7.54 (m, 1H), 4.86 (s,2H), 1.65 (s, 6H), 1.21 (s, 9H). A04M1B01 ¹H NMR (400 MHz, DMSO-d₆): δ12.45 (bs, 1H), 10.89 (s, 1H), 7.7 (m, 1H), 7.38 (m, 1H), 7.20 (s, 1H),4.89 (s, 2H), 1.68 (s, 6H), 1.24 (s, 9H). A05M1B01 ¹H NMR (400 MHz,DMSO-d₆): δ 12.54 (bs, 1H), 11.07 (s, 1H), 7.76 (s, 2H), 7.51 (s, 1H),4.89 (s, 2H), 1.68 (s, 6H), 1.25 (s, 9H). A06M1B01 ¹H NMR (400 MHz,DMSO-d₆): δ 12.43 (bs, 1H), 10.98 (s, 1H), 7.98 (d, 2H, J = 8.0 Hz),7.54 (d, 2H, J = 8.0 Hz), 4.86 (s, 2H), 1.65 (s, 6H), 1.21 (s, 9H).A07M1B01 ¹H NMR (400 MHz, DMSO-d₆): δ 12.47 (bs, 1H), 11.16 (s, 1H),8.16 (d, 2H, J = 7.9 Hz), 7.85 (d, 2H, J = 7.9 Hz), 4.88 (s, 2H), 1.65(s, 6H), 1.21 (s, 9H). A08M1B01 ¹H NMR (400 MHz, DMSO-d₆): δ 12.50 (bs,1H), 11.17 (s, 1H), 9.13 (s, 1H,), 8.76 (m, 1H), 8.33 (m, 1H) 7.51 (m,1H), 4.91 (s, 2H), 1.69 (s, 6H), 1.25 (s, 9H). A09M1B01 ¹H NMR (400 MHz,DMSO-d₆): δ 12.54 (bs, 1H), 11.25 (s, 1H), 8.75 (d, 2H), 7.91 (d, 2H),4.92 (s, 2H), 1.69 (s, 6H), 1.25 (s, 9H). A10M1B01 ¹H NMR (400 MHz,DMSO-d₆): δ 12.47 (bs, 1H), 11.00 (s, 1H), 8.12 (m, 1H), 7.86 (m, 1H),7.12 (m, 1H), 4.86 (s, 2H), 1.68 (s, 6H), 1.25 (s, 9H). A11M1B01 ¹H NMR(400 MHz, DMSO-d₆): δ 12.11 (bs, 1H), 10.77 (s, 1H), 8.45 (s, 1H), 7.69(m, 2H), 4.89 (s, 2H), 1.68 (s, 6H), 1.25 (s, 9H). A12M1B01 ¹H NMR (400MHz, DMSO-d₆): δ 12.22 (bs, 1H), 10.31 (s, 1H), 4.76 (s, 2H), 2.12 (m,3H), 1.61 (s, 6H), 1.19 (s, 9H), 0.87 (d, 6H, J = 6.5 Hz). A13M1B01 ¹HNMR (400 MHz, DMSO-d₆): δ 12.21 (bs, 1H), 10.19 (bs, 1H), 4.80 (s, 2H),3.28 (m, 1H), 2.25-1.70 (m, 6H), 1.60 (s, 6H), 1.20 (s, 9H). A14M1B01 ¹HNMR (400 MHz, DMSO-d₆): δ 12.35 (bs, 1H), 10.38 (bs, 1H), 4.75 (s, 2H),1.82 (m, 1H), 1.60 (s, 6H), 1.20 (s, 9H), 0.78 (m, 4H). A15M1B01 ¹H NMR(400 MHz, DMSO-d₆): δ 12.3 (bs, 1H), 9.89 (s, 1H), 4.80 (s, 2H), 1.64(s, 6H), 1.23 (s, 9H), 1.21 (s, 9H). A16M1B01 ¹H NMR (400 MHz, DMSO-d₆):δ 12.35 (bs, 1H), 11.02 (s, 1H), 8.09 (d, 2H), J = 8.2 Hz), 7.47 (d, 2H,J = 8.2 Hz), 4.85 (s, 2H), 1.64 (s, 6H), 1.21 (s, 9H). A19M1B01 ¹H NMR(400 MHz, DMSO-d₆): δ 12.48 (bs, 1H), 10.82 (s, 1H), 8.43 (m, 1H), 7.45(m, 1H), 6.70 (m, 1H), 4.85 (s, 2H), 1.67 (s, 6H), 1.25 (s, 9H).A20M1B01 ¹H NMR (400 MHz, DMSO-d₆): δ 12.26 (bs, 1H), 10.38 (s, 1H),4.80 (s, 2H), 3.04 (m, 2H), 2.52 (m, 3H), 1.64 (m, 10H), 1.23 (s, 9H).A22M1B01 ¹H NMR (400 MHz, DMSO-d₆): δ 12.43 (bs, 1H), 11.06 (s, 1H),8.3-7.6 (m, 7H), 4.99 (s, 2H), 1.71 (m, 6H), 1.26 (s, 9H). A23M1B01 ¹HNMR (400 MHz, DMSO-d₆): δ 12.48 (bs, 1H), 11.07 (s, 1H), 8.68 (s, 1H),8.08 (m, 4H), 7.66 (m, 2H), 4.95 (s, 2H), 1.70 (m, 6H), 1.27 (s, 9H).A24M1B01 ¹H NMR (400 MHz, DMSO-d₆): δ 12.05 (bs, 1H), 8.87 (s, 1H), 7.19(m, 4H), 6.91 (bs, 1H), 4.73 (s, 2H), 4.32 (d, 2H, J = 5.85 Hz), 2.30(s, 3H), 1.63 (s, 6H), 1.22 (s, 9H). A25M1B01 ¹H NMR (400 MHz, DMSO-d₆):δ 12.31-12.05 (2bs, 1H), 8.48 (s, 1H), 7.30 (m, 5H), 7.00 (bs, 1H), 4.73(s, 2H), 4.33 (d, 2H), J = 5.85 Hz), 1.63 (s, 6H), 1.22 (s, 9H).A28M1B01 ¹H NMR (400 MHz, DMSO-d₆): δ 12.07 (bs, 1H), 8.99 (s, 1H), 4.72(s, 2H), 3.40 (m, 4H), 1.63 (s, 6H), 1.5 (m, 6H), 1.22 (s, 9H). A29M1B01¹H NMR (400 MHz, DMSO-d₆): δ 12.36 (bs, 1H), 10.08 (s, 1H), 4.82 (s,2H), 3.15 (bs, 2H), 2.32 (s, 6H), 1.65 (s, 6H), 1.23 (s, 9H). A02M2B01¹H NMR (400 MHz, DMSO-d₆): δ 12.29 (bs, 1H), 11.05 (s, 1H), 7.9-7.35 (m,3H), 5.03 (s, 2H), 2.29 (m, 2H), 1.24 (s, 9H), 0.84 (m, 2H). A04M2B01 ¹HNMR (400 MHz, DMSO-d₆): δ 12.21 (bs, 1H), 10.90 (s, 1H), 7.79 (m, 1H),7.40 (m, 1H), 7.21 (m, 1H), 5.03 (s, 2H), 2.29 (m, 2H), 1.24 (s, 9H),0.83 (m, 2H). A05M2B01 ¹H NMR (400 MHz, DMSO-d₆): δ 12.30 (bs, 1H),11.17 (s, 1H), 7.77 (s, 2H), 7.51 (s, 1H), 5.04 (s, 2H), 2.29 (m, 2H),1.24 (s, 9H), 0.84 (m, 2H). A06M2B01 ¹H NMR (400 MHz, DMSO-d₆): δ 12.28(bs, 1H), 11.04 (s, 1H), 8.03 (d, 2H, J = 8.0 Hz), 7.61 (d, 2H, J = 8.0Hz), 5.03 (s, 2H), 2.29 (m, 2H), 1.24 (s, 9H), 0.83 (m, 2H). A07M2B01 ¹HNMR (400 MHz, DMSO-d₆): δ 12.32 (bs, 1H), 11.22 (s, 1H), 8.21 (d, 2H, J= 7.9 Hz), 7.91 (d, 2H, J = 7.9 Hz), 5.05 (s, 2H), 2.29 (m, 2H), 1.24(s, 9H), 0.84 (m, 2H). A10M2B01 ¹H NMR (400 MHz, DMSO-d₆): δ 12.23 (bs,1H), 11.02 (s, 1H), 8.10 (m, 1H), 7.87 (m, 1H), 7.22 (m, 1H), 5.01 (s,2H), 2.29 (m, 2H), 1.24 (s, 9H), 0.84 (m, 2H). A12M2B01 ¹H NMR (400 MHz,DMSO-d₆): δ 12.03 (bs, 1H), 10.36 (bs, 1H), 4.95 (s, 2H), 2.26 (m, 2H),2.17 (m, 2H), 2.09 (m, 1H), 1.22 (s, 9H), 0.93 (m, 6H), 0.80 (m, 2H).A13M2B01 ¹H NMR (400 MHz, DMSO-d₆): δ 12.05 (bs, 1H), 10.28 (bs, 1H),4.96 (s, 2H), 3.32 (m, 1H), 2.25 (m, 8H), 1.23 (s, 9H), 0.78 (m, 2H).A14M2B01 ¹H NMR (400 MHz, DMSO-d₆): δ 12.03 (bs, 1H), 10.72 (bs, 1H),4.91 (s, 2H), 2.25 (m, 2H), 1.82 (m, 1H), 1.20 (s, 9H), 0.80 (m, 6H).A15M2B01 ¹H NMR (400 MHz, DMSO-d₆): δ 12.01 (bs, 1H), 9.92 (s, 1H), 4.94(s, 2H), 2.25 (m, 2H), 1.22 (s, 18H), 0.78 (m, 2H). A19M2B01 ¹H NMR (400MHz, DMSO-d₆): δ 12.21 (bs, 1H), 10.82 (s, 1H), 7.92 (m, 1H), 7.49 (m,1H), 6.69 (m, 1H), 5.01 (s, 2H), 2.29 (m, 2H), 1.24 (s, 9H), 0.83 (m,2H). A27M2B01 ¹H NMR (400 MHz, DMSO-d₆): δ 11.98 (bs, 1H), 9.02 (s, 2H),7.45 (m, 1H), 7.33 (m, 1H), 7.13 (m, 1H), 6.81 (m, 1H), 4.96 (s, 2H),2.27 (m, 2H), 1.23 (s, 9H), 0.81 (m, 2H). A28M2B01 ¹H NMR (400 MHz,DMSO-d₆): δ 11.83 (bs, 1H), 9.03 (s, 1H), 4.87 (s, 2H), 3.41 (m, 4H),2.23 (m, 2H), 1.58 (m, 2H), 1.49 (m, 4H), 1.22 (s, 9H), 0.76 (m, 2H).A30M1B01 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.2 (s, 9H) 1.7 (s, 6H) 4.9(s, 2H) 7.4-8.1 (m, 5H) 11.2 (s, 1H) 12.5 (s, 1H) A31M1B01 ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.2 (s, 9H) 1.7 (s, 6H) 1.7 (m, 2H) 2.0 (m, 2H) 2.2(s, 3H) 2.3 (m, 2H) 2.7 (m, 2H) 4.5 (m, 1H) 4.9 (s, 2H) 7.0 (d, J = 7.9Hz, 2H) 8.0 (d, J = 7.9 Hz, 2H) 10.7 (s, 1H) 12.4 (s, 1H) A32M1B01.HCl¹H NMR (400 MHz, DMSO-d₆): (mixture of two conformers) δ ppm 1.25 (s,18H) 1.68 (s, 12H) 1.84 (m, 2H) 2.07 (m, 4H) 2.29 (d, J = 14.0 Hz, 2H)2.80 (d, J = 5.0 Hz, 3H) 2.82 (d, J = 5.0 Hz, 3H) 3.11 (m, 2H) 3.20 (m,2H) 3.40 (m, 2H) 3.52 (d, J = 14.0 Hz, 2H) 4.67 (m, 1H) 4.87 (m, 1H)4.89 (s, 4H) 7.21 (dd, J = 8.8, 2.3 Hz, 1H) 7.25 (dd, J = 8.8, 2.3 Hz,1H) 7.45 (m, 2H) 7.5-7.7 (m, 4H) 9.90 (bs, 1H) 9.97 (bs, 1H) 10.93 (s,2H) 12-13 (bs, 2H). A33M1B01.2HCl ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.3(s, 9H) 1.7 (s, 6H) 2.8 (s, 3H) 3.4 (m, 10H) 4.9 (s, 2H) 7.6 (s, 2H) 8.1(d, J = 7.9 Hz, 2H) 10.4 (s, 1H) 11.0 (s, 1H) A34M1B01.HCl ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.3 (s, 9H) 1.7 (s, 6H) 1.9 (m, 4H) 3.4 (m, 4H) 4.9(m, 1H) 4.9 (s, 2H) 7.0 (d, J = 9.1 Hz, 2H) 7.9 (d, J = 9.0 Hz, 2H) 10.6(s, 1H) A35M1B01 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.2 (s, 9H) 1.6 (s,6H) 2.3 (s, 3H) 2.5 (m, 4H) 3.1 (m, 2H) 3.3 (m, 2H) 4.8 (s, 2H) 6.9 (d,J = 8.2 Hz, 2H) 7.9 (d, J = 8.4 Hz, 2H) 10.5 (s, 1H) 12.3 (s, 1H)A36M1B01 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.2 (s, 9H) 1.6 (s, 6H) 2.1(m, 2H) 2.5 (t, J = 8.0 Hz, 2H) 3.9 (t, J = 7.0 Hz, 2H) 4.8 (s, 2H) 7.8(d, J = 8.9 Hz, 2H) 8.0 (d, J = 8.8 Hz, 2H) 10.8 (s, 1H) 12.4 (s, 1H)A37M1B01 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.3 (s, 9H) 1.7 (s, 6H) 4.1(m, 2H) 4.5 (m, 2H) 4.9 (s, 2H) 7.7 (d, J = 8.2 Hz, 2H) 8.1 (d, J = 7.8Hz, 2H) 10.9 (s, 1H) 12.4 (s, 1H) A38M1B01 ¹H NMR (400 MHz, DMSO-d₆): δppm 1.3 (s, 9H) 1.7 (s, 6H) 3.8 (s, 3H) 3.9 (s, 3H) 4.9 (s, 2H) 7.1 (d,J = 8.5 Hz, 1H) 7.6 (d, J = 1.2 Hz, 1H) 7.7 (dd, J = 8.5, 2.0 Hz, 1H)10.8 (s, 1H) 12.4 (s, 1H) A38M2B01 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.8(m, 2H) 1.2 (s, 9H) 2.3 (m, 2H) 3.8 (s, 3H) 3.9 (s, 3H) 5.0 (s, 2H) 7.1(m, 1H) 7.6 (m, 1H) 7.7 (m, 1H) 10.8 (s, 1H) 12.2 (s, 1H) A39M1B01 ¹HNMR (400 MHz, DMSO-d₆): δ ppm 1.3 (s, 9H) 1.7 (s, 6H) 4.9 (s, 2H) 7.5(s, 1H) 8.0 (d, J = 7.3 Hz, 2H) 8.05 (d, J = 7.3 Hz, 2H) 8.11 (s, 1H)11.0 (s, 1H) 12.5 (s, 1H) A40M1B01 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.2(s, 9H) 1.6 (s, 3H) 4.9 (s, 2H) 8.0 (d, J = 8.4 Hz, 2H) 8.1 (d, J = 8.5Hz, 2H) 11.2 (s, 1H) 12.5 (s, 1H) A41M1B01 ¹H NMR (400 MHz, DMSO-d₆): δppm 1.2 (s, 9H) 1.7 (s, 6H) 4.9 (s, 2H) 7.7 (t, J = 7.6 Hz, 1H) 8.1 (d,J = 7.6 Hz, 1H) 8.3 (d, J = 7.9 Hz, 1H) 8.4 (s, 1H) 11.2 (s, 1H) 12.5(s, 1H) A43M1B01 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.2 (s, 9H) 1.7 (s,6H) 4.9 (s, 2H) 7.3 (m, 2H) 7.6 (m, 1H) 7.7 (m, 1H) 10.9 (s, 1H) 12.4(s, 1H) A44M1B01 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.25 (s, 9H) 1.68 (s,6H) 3.85 (s, 3H) 4.88 (s, 2H) 7.03 (m, 2H) 8.01 (d, J = 8.29 Hz, 2H)10.74 (s, 1H) 12.40 (s, 1H) A45M1B01 ¹H NMR (400 MHz, DMSO-d₆): δ ppm1.3 (s, 9H) 1.7 (s, 6H) 3.8 (s, 3H) 4.9 (s, 2H) 7.2 (m, 1H) 7.4 (m, 1H)7.6 (m, 2H) 10.9 (s, 1H) 12.5 (s, 1H) A46M1B01 ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.3 (s, 9H) 1.7 (s, 6H) 4.0 (s, 3H) 4.9 (s, 2H) 7.1 (t,J = 7.4 Hz, 1H) 7.2 (d, J = 8.3 Hz, 1H) 7.6 (t, J = 7.8 Hz, 1H) 7.8 (dd,J = 7.7, 1.7 Hz, 1H) 10.3 (s, 1H) 12.4 (s, 1H) A47M1B01 ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.2 (s, 9H) 1.6 (s, 6H) 3.6 (s, 2H) 4.8 (s, 2H) 7.25 (m,1H) 7.32 (m, 4H) 10.7 (s, 1H) 12.3 (s, 1H) A48M1B01 ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.16 (s, 9H) 1.60 (s, 6H) 3.78 (s, 2H) 4.75 (s, 2H) 7.47(m, 3H) 7.80 (s, 1H) 7.86 (m, 3H) 10.74 (s, 1H) 12.30 (s, 1H) A49M1B01¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.23 (s, 9H) 1.67 (m, 14H) 2.79 (m, 1H)4.80 (s, 2H) 10.37 (s, 1H) 12.23 (s, 1H) A50M1B01 ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.32 (m, 6H) 1.23 (s, 9H) 1.74 (m, 4H) 1.64 (s, 6H) 2.36(m, 1H) 4.79 (s, 2H) 10.30 (s, 1H) 12.21 (s, 1H) A51M1B01 ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.2 (s, 9H) 1.6 (s, 6H) 2.0 (m, 4H) 3.9 (m, 2H) 4.4(dd, J = 8.2, 5.6 Hz, 1H) 4.8 (s, 2H) 10.1 (s, 1H) 12.3 (s, 1H)A52M1B01.HCl ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.2 (s, 9H) 1.6 (s, 6H)1.9 (m, 4H) 2.6 (m, 1H) 2.8 (m, 3H) 3.0 (m, 2H) 3.4 (m, 2H) 4.8 (s, 2H)9.6 (s, 1H) 10.6 (s, 1H) 12.4 (s, 1H) A53M1B01 ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.2 (s, 9H) 1.4 (m, 1H) 1.5 (m, 1H) 1.6 (s, 6H) 1.7 (m,2H) 2.0 (s, 3H) 2.6 (m, 2H) 3.0 (t, J = 13.0 Hz, 1H) 3.8 (d, J = 13.7Hz, 1H) 4.4 (d, J = 12.9 Hz, 1H) 4.8 (s, 2H) 10.4 (s, 1H) 12.3 (s, 1H)A54M1B01 ¹H NMR (400 MHz, DMSO-d₆): δ 12.52 (bs, 1H), 11.23 (s, 1H),8.30 (m, 2H), 7.96 (m, 1H), 7.76 (m, 1H), 4.91 (bs, 2H), 1.69 (s, 6H),1.25 (s, 9H). A01M1B02 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.65 (s, 6H),2.0 (m, 4H) 3.79 (m, 2H), 4.53 (t, 1H), 4.83 (m, 2H), 7.3 (m, 2H), 8.05(m, 2H), 10.92 (s, 1H), 12.45 (s, 1H). A48M1B02 ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.59 (s, 3H) 1.60 (s, 3H) 1.86 (m, 4H) 3.70 (m, 2H) 3.76(s, 2H) 4.44 (t, J = 6.52 Hz, 1H) 4.55 (d, J = 12.44 Hz, 1H) 4.72 (d, J= 12.56 Hz, 1H) 7.46 (m, 3H) 7.78 (s, 1H) 7.86 (m, 3H) 10.74 (s, 1H)12.32 (s, 1H) A03M1B14 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.7 (s, 6H) 2.0(m, 4H) 3.8 (m, 2H) 4.6 (t, J = 6.6 Hz, 1H) 4.7 (d, J = 12.4 Hz, 1H) 4.9(d, J = 12.4 Hz, 1H) 7.6 (ddd, J = 10.5, 8.5, 8.4 Hz, 1H) 7.9 (m, 1H)8.1 (m, 1H) 11.1 (s, 1H) 12.5 (s, 1H) α_(D) +24.5 (c = 1.08, MeOH)A12M1B14 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.92 (d, J = 6.58 Hz, 6H) 1.65(d, J = 2.44 Hz, 6H) 1.96 (m, 5H) 2.16 (d, J = 6.95 Hz, 2H) 3.80 (m, 2H)4.53 (dd, J = 6.95, 6.10 Hz, 1H) 4.68 (m, 2H) 10.37 (s, 1H) 12.30 (s,1H) α_(D) +24.0 (c = 1.00, MeOH) A13M1B14 ¹H NMR (400 MHz, DMSO-d₆): δppm 1.64 (s, 6H) 1.97 (m, 10H) 3.25 (m, 1H) 3.80 (m, 2H) 4.55 (t, J =6.58 Hz, 1H) 4.70 (m, 2H) 10.26 (s, 1H) 12.28 (s, 1H) α_(D) +24.7 (c =1.09, MeOH) A32M1B14.HCl ¹H NMR (400 MHz, DMSO-d₆): (mixture of twoconformers) δ ppm 1.68 (s, 12H) 1.8-2.1 (m, 10H) 2.30 (d, J = 14.0 Hz,2H) 2.80 (d, J = 5.0 Hz, 3H) 2.83 (d, J = 5.0 Hz, 3H) 3.1-3.3 (m, 4H)3.45 (m, 2H) 3.52 (d, J = 14.0 Hz, 2H) 3.7-3.8 (m, 4H) 4.56 (dd, J =7.0, 6.0 Hz, 2H) 4.66 (m, 1H) 4.71, 4.88 (2d, J = 13 Hz, 4H) 4.87 (m,1H) 7.21 (dd, J = 8.0, 2.3 Hz, 1H) 7.26 (dd, J = 8.8, 2.3 Hz, 1H) 7.46(m, 2H) 7.5-7.7 (m, 4H) 9.89 (bs, 2H) 10.94 (s, 2H) 12-13 (bs, 2H).α_(D) +17.4 (c = 1.02, MeOH) A33M1B14.2HCl ¹H NMR (400 MHz, DMSO-d₆): δppm 1.7 (s, 3H) 1.7 (s, 3H) 2.0 (m, 4H) 2.8 (s, 3H) 3.7 (m, 10H) 3.8 (m,2H) 4.6 (dd, J = 7.3, 5.9 Hz, 1H) 4.7 (d, J = 12.4 Hz, 1H) 4.9 (d, J =12.4 Hz, 1H) 7.6 (d, J = 7.3 Hz, 2H) 8.0 (d, J = 8.2 Hz, 2H) 10.3 (s,1H) 11.0 (s, 1H) α_(D) +14.7 (c = 1.09, MeOH) A31M1B14 ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.7 (s, 6H) 2.1 (m, 8H) 2.8 (m, 3H) 3.3 (m, 4H) 3.8 (m,2H) 4.6 (dd, J = 7.2, 6.1 Hz, 1H) 4.7 (m, 1H) 4.7 (d, J = 12.6 Hz, 1H)4.9 (d, J = 12.6 Hz, 1H) 7.1 (m, 2H) 8.0 (m, 2H) 9.9 (m, 1H) 10.8 (s,1H) 12.2 (s, 1H) α_(D) (as hydrochloride salt) +17.0 (c = 1.08, MeOH)A01M2B14 ¹H NMR (400 MHz, DMSO-d₆): δ 12.25 (bs, 1H), 10.98 (bs, 1H),8.11 (m, 2H), 7.34 (m, 2H), 4.96 (m, 2H), 4.56 (t, 1H), 3.77 (m, 2H)2.24 (m, 2H), 2.03 (m, 2H), 1.87 (m, 2H), 0.93 (s, 2H). α_(D) +15.9 (c =1.06, MeOH) A12M1B21.HCO₂H ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.9 (d, J =6.6 Hz, 6H) 1.2 (s, 3H) 1.5 (m, 2H) 1.7 (s, 6H) 2.2 (m, 12H) 4.7 (s, 2H)8.2 (s, 1H) 10.4 (s, 1H) 12.3 (s, 1H) A01M1B21.HCl ¹H NMR (400 MHz,DMSO-d₆): (mixture of two conformers) δ ppm 1.29 (s, 3H) 1.38 (s, 3H)1.65 (m, 2H) 1.70 (s, 3H) 1.73 (s, 3H) 1.95 (d, J = 14.0 Hz, 2H) 2.08(m, 2H) 2.46 (d, J = 14.0 Hz, 2H) 2.74 (d, J = 5.0 Hz, 3H) 2.79 (d, J =5.0 Hz, 3H) 2.87 (m, 2H) 3.13 (m, 2H) 3.3-3.5 (m, 4H) 4.86 (s, 4H) 7.35(t, J = 8.9 Hz, 4H) 8.09 (dd, J = 8.9, 5.5 Hz, 4H) 9.5 (bs, 1H) 9.7 (bs,1H) 11.01 (s, 1H) 11.03 (s, 1H) 12-13 (bs, 2H). A01M1B22.HCl ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.69 (s, 6H) 2.16 (m, 6H) 3.32 (m, 6H) 4.89 (s, 2H)7.36 (t, J = 8.66 Hz, 2H) 8.08 (dd, J = 9.02, 5.49 Hz, 2H) 9.58 (s, 1H)11.01 (s, 1H) 12.55 (s, 1H) A48M1B43 ¹H NMR (400 MHz, DMSO-d₆): δ ppm1.16 (t, J = 7.13 Hz, 3H) 1.57 (s, 6H) 3.76 (s, 2H) 4.00 (q, J = 7.07Hz, 2H) 4.38 (s, 2H) 7.48 (m, 3H) 7.79 (s, 1H) 7.87 (m, 3H) 10.73 (s,1H) 12.32 (s, 1H)

EXAMPLE 18N-{6,6-dimethyl-5-[(1-methylpiperidin-4-yl)carbonyl]-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-fluorobenzamide

Ethyl3-[(4-fluorobenzoyl)amino]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylatehydrochloride (0.5 g, 1.3 mmol), in dichloromethane (25 ml), was treatedwith N,N-diisopropylethylamine (1.13 ml, 6.5 mmol, 5 eq) and TBTU (0.542g, 1.69 mmol, 1.3 eq), at room temperature for 1 hour, and then1-methyl-piperidine-4-carboxylic acid hydrochloride (0.29 g, 1.61 mmol,1.2 eq) was added. The reaction was stirred overnight (TLC: CH₂Cl₂/MeOH90/10). The solution was washed with saturated sodium hydrogencarbonateaqueous solution and brine, the organic phase was dried over sodiumsulfate and concentrated. The residue was dissolved in methanol (16 ml),treated with TEA (2 ml, 14.3 mmol, 11 eq) and stirred overnight at roomtemperature. (TLC: CH₂Cl₂/MeOH/NH₄OH 90/10/1). After evaporation, thesolid was purified by flash chromatography (eluent: CH₂Cl₂/MeOH/NH₄OH90/10/2). The solid was treated with diisopropylether and filtered toafford 0.36 g of the title compound in 69% yield.

ESI MS: m/z 400 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 12.48 (bs, 1H), 10.97 (bs, 1H), 8.09 (m,2H), 7.35 (m, 2H), 4.75 (bs, 2H), 2.87 (m, 2H), 2.40 (m, 1H), 2.24 (s,3H), 2.05 (m, 2H), 1.67 (m, 10H).

By working in an analogous manner the following compound was prepared:

N-[5-[(1-methylpiperidin-4-yl)carbonyl]-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-6-spirocyclopropan-3-yl]-4-fluorobenzamide

ESI MS: m/z 398 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 12.20 (bs, 1H), 11.00 (s, 1H), 8.10 (m,2H), 7.36 (m, 2H), 4.91 (s, 2H), 2.84 (m, 2H), 2.40 (m, 1H), 2.23 (m,5H), 2.0 (m, 2H), 1.65 (m, 4H), 0.89 (m, 2H).

By working in analogous manner and by using the proper starting materialand any suitable reactant, as per the aforementioned process, additionalcompounds of formula (Ia) and (Ib) were also prepared, as reported inthe following table IV

TABLE IV A01M1B03.HCl ¹H NMR (400 MHz, DMSO-d₆): δ 11.02 (s, 1H), 9.56(bs, 1H), 8.11 (m, 2H), 7.36 (m, 2H), 4.80 (bs, 2H), 3.43 (m, 2H), 3.07(m, 2H) 2.75 (d, 3H), 2.69 (m, 1H), 1.94 (m, 4H), 1.67 (m, 6H).A02M1B03.HCl ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.68 (m, 6H) 1.93 (m, 4H)2.74 (m, 4H) 3.07 (m, 2H) 3.42 (m, 2H) 4.81 (s, 2H) 7.46 (m, 1H) 7.59(td, J = 7.96, 5.91 Hz, 1H) 7.82 (ddd, J = 10.00, 2.32, 1.59 Hz, 1H)7.87 (dt, J = 7.90, 1.11 Hz, 1H) 9.49 (s, 1H) 11.09 (s, 1H) A03M1B03.HCl¹H NMR (400 MHz, DMSO-d6) δ ppm 1.69 (m, 6H) 1.93 (m, 4H) 2.74 (m, 4H)3.02 (m, 2H) 3.34 (m, 2H) 4.79 (s, 2H) 7.40 (m, 1H) 7.53 (m, 1H) 7.60(m, 1H) 9.48 (s, 1H) 11.11 (s, 1H) A04M1B03 ¹H NMR (400 MHz, DMSO-d₆): δ12.48 (bs, 1H), 10.93 (s, 1H), 7.75 (m, 1H), 7.40 (m, 1H), 7.22 (m, 1H),4.75 (bs, 2H), 2.85 (m, 2H), 2.38 (m, 1H), 2.21 (bs, 3H), 2.01 (m, 2H),1.67 (m, 10H). A05M1B03.HCl ¹H NMR (400 MHz, DMSO-d₆): δ 12.6 (bs, 1H),11.19 (s, 1H), 9.49 (bs, 1H), 7.72 (m, 2H), 7.51 (m, 1H), 4.80 (bs, 2H),3.46 (m, 2H), 3.06 (m, 2H), 2.76 (bd, 3H), 2.71 (m, 1H), 1.97 (m, 2H),1.81 (m, 2H), 1.67 (s, 6H). A06M1B03.HCl ¹H NMR (400 MHz, DMSO-d₆): δ12.55 (bs, 1H), 11.06 (s, 1H), 9.66 (bs, 1H), 8.02 (m, 2H), 7.63 (m,2H), 4.81 (s, 2H), 3.4 (m, 2H), 3.01 (m, 2H), 2.75 (bs, 3H), 2.68 (m,1H), 1.95 (m, 2H), 1.84 (m, 2H), 1.67 (s, 6H). A07M1B03.HCl ¹H NMR (400MHz, DMSO-d₆): δ 12.60 (bs, 1H), 11.25 (s, 1H), 9.50 (bs, 1H), 8.19 (d,2H, J = 7.9 Hz), 7.92 (d, 2H, J = 7.9 Hz), 4.83 (s, 2H), 3.4 (m, 2H),3.01 (m, 2H), 2.78 (bd, 3H), 2.75 (m, 1H), 1.9 (m, 2H), 1.8 (m, 2H),1.67 (s, 6H). A09M1B03.2HCl 1H NMR (400 MHz, DMSO-d6) δ ppm 11.38 (s,1H), 9.68 (s, 1H), 8.83 (d, J = 6.22 Hz, 2H), 7.98 (d, J = 6.22 Hz, 2H),4.82 (s, 2H), 3.4 (m, 2H), 3.07 (m, 2H), 2.75 (bd, 3H), 2.69 (m, 1H),1.90 (m, 4H), 1.69 (s, 6H) A10M1B03.HCl ¹H NMR (400 MHz, DMSO-d₆): δ12.52 (bs, 1H), 11.07 (s, 1H), 9.50 (bs, 1H), 8.12 (m, 1H), 7.86 (m,1H), 7.22 (m, 1H), 4.79 (bs, 2H), 3.42 (m, 2H), 3.08 (m, 2H), 2.76 (m,4H), 1.94 (m, 2H), 1.82 (m, 2H), 1.67 (s, 6H). A11M1B03.HCl ¹H NMR (400MHz, DMSO-d₆): δ 12.41 (bs, 1H), 10.83 (s, 1H), 9.55 (s, 1H), 8.43 (dd,J = 2.80, 1.46 Hz, 1H), 7.67 (dd, J = 5.12, 1.46 Hz, 1H), 7.65 (dd, J =5.12, 2.80 Hz, 1H), 4.79 (s, 2H), 3.47 (m, 2H), 3.06 (m, 2H), 2.74 (m,4H), 1.88 (m, 4H), 1.68 (s, 6H). A12M1B03 ¹H NMR (400 MHz, DMSO-d₆): δ12.29 (bs, 1H), 10.40 (s, 1H), 4.65 (s, 2H), 2.86 (m, 2H), 2.35 (m, 1H),2.22 (bs, 3H), 2.17 (d, 2H, J = 7.07 Hz), 2.02 (m, 3H), 1.64 (m, 10H),0.92 (d, 6H, J = 6.6 Hz). A12M1B03.HCl ¹H NMR (400 MHz, DMSO-d₆): δ12.29 (s, 1H), 10.41 (bs, 1H), 9.57 (s, 1H), 4.71 (s, 2H), 3.46 (m, 2H),3.07 (m, 2H), 2.75 (bd, 3H), 2.69 (m, 1H), 2.17 (d, 2H, J = 6.95 Hz),2.04 (m, 1H), 1.92 (m, 4H), 1.67 (s, 6H), 0.92 (d, 6H, J = 6.7 Hz).A13M1B03 ¹H NMR (400 MHz, DMSO-d₆): δ 12.29 (bs, 1H), 10.27 (s, 1H),4.69 (s, 2H), 3.35 (m, 1H), 2.87 (m, 2H), 2.38 (m, 1H), 2.24 (bs, 3H),2.20 (m, 6H), 2.07 (m, 2H), 1.63 (m, 10H). A13M1B03.HCl ¹H NMR (400 MHz,DMSO-d₆): δ 12.34 (bs, 1H), 10.30 (s, 1H), 9.48 (bs, 1H), 4.75 (s, 2H),3.47 (m, 2H), 3.31 (m, 1H), 3.09 (m, 2H), 2.75 (bd, 3H), 2.70 (m, 1H),2.23-1.76 (m, 10H), 1.64 (s, 6H). A13M1B03.CH₃SO₃H ¹H NMR (400 MHz,DMSO-d₆): δ 12.33 (bs, 1H), 10.31 (s, 1H), 9.21 (bs, 1H), 4.75 (s, 2H),3.44 (m, 2H), 3.24 (m, 1H), 3.09 (m, 2H), 2.78 (bd, 3H), 2.72 (m, 1H),2.35 (s, 3H), 2.23-1.72 (m, 10H), 1.64 (s, 6H). A14M1B03 ¹H NMR (400MHz, DMSO-d₆): δ 12.30 (bs, 1H), 10.72 (s, 1H), 4.63 (s, 2H), 2.86 (m,2H), 2.34 (m, 1H), 2.23 (bs, 3H), 2.04 (m, 2H), 1.83 (m, 1H), 1.63 (m,10H), 0.79 (m, 4H). A16M1B03 ¹H NMR (400 MHz, DMSO-d₆): δ 12.30 (bs,1H), 11.10 (s, 1H), 8.13 (d, 2H, J = 7.9 Hz), 7.51 (d, 2H, J = 7.9 Hz),4.75 (s, 2H), 2.86 (m, 2H), 2.39 (m, 1H), 2.22 (s, 3H), 2.03 (m, 2H),1.69 (m, 10H). A17M1B03 ¹H NMR (400 MHz, DMSO-d₆): δ 12.48 (bs, 1H),10.98 (s, 1H), 7.79 (m, 1H), 7.61 (m, 1H), 7.54 (m, 1H), 7.45 (m, 2H),7.25 (m, 2H), 7.10 (m, 2H), 4.72 (s, 2H), 2.82 (m, 2H), 2.34 (m, 1H),2.19 (s, 3H), 1.96 (m, 2H), 1.66 (m, 10H). A19M1B03.HCl ¹H NMR (400 MHz,DMSO-d₆): δ 10.87 (s, 1H), 9.55 (bs, 1H), 7.93 (dd, J = 1.71, 0.85 Hz,1H), 7.44 (dd, J = 3.48, 0.79 Hz, 1H), 6.70 (dd, J = 3.48, 1.77 Hz, 1H),4.77 (bs, 2H), 3.30 (m, 2H), 3.05 (m, 2H), 2.74 (m, 4H), 1.93 (m, 2H),1.84 (m, 2H), 1.67 (s, 6H). A21M1B03 ¹H NMR (400 MHz, DMSO-d₆): δ 12.40(bs, 1H), 11.00 (s, 1H), 8.65 (d, 1H, J = 2.5 Hz), 8.16 (d, 2H, J = 8.3Hz), 8.01 (d, 2H, J = 8.3 Hz), 7.83 (d, 1H, J = 1.6 Hz), 6.62 (dd, 1H, J= 2.5 Hz), 4.47 (s, 2H), 2.86 (m, 2H), 2.38 (m, 1H), 2.22 (s, 3H), 2.03(m, 2H), 1.69 (m, 10H). A22M1B03 ¹H NMR (400 MHz, DMSO-d₆): δ 12.44 (bs,1H), 11.12 (s, 1H), 8.25 (m, 1H), 8.09 (m, 1H), 8.03 (m, 1H), 7.75 (m,1H), 7.60 (m, 3H), 4.82 (bs, 2H), 2.84 (m, 2H), 2.38 (m, 1H), 2.19 (s,3H), 1.98 (m, 2H), 1.70 (m, 10H). A23M1B03 ¹H NMR (400 MHz, DMSO-d₆): δ12.51 (bs, 1H), 11.11 (s, 1H), 8.67 (bs, 1H), 8.07 (m, 4H), 7.66 (m,2H), 4.80 (bs, 2H), 2.86 (m, 2H), 2.38 (m, 1H), 2.22 (s, 3H), 2.02 (m,2H), 1.69 (m, 10H). A24M1B03 ¹H NMR (400 MHz, DMSO-d₆): δ 12.11 (bs,1H), 8.82 (s, 1H), 7.19 (m, 4H), 6.81 (m, 1H), 4.61 (s, 2H), 4.29 (d,2H, J = 5.80 Hz), 2.85 (m, 2H), 2.33 (m, 1H), 2.30 (s, 3H), 2.21 (s,3H), 2.03 (m, 2H), 1.63 (m, 10H). A25M1B03 ¹H NMR (400 MHz, DMSO-d₆): δ12.08 (bs, 1H), 8.85 (s, 1H), 7.30 (m, 5H), 6.91 (bs, 1H), 4.61 (s, 2H),4.32 (d, 2H, J = 5.90 Hz), 2.86 (m, 2H), 2.35 (m, 1H), 2.30 (s, 3H),2.05 (m, 2H), 1.63 (m, 10H). A26M1B03 ¹H NMR (400 MHz, DMSO-d₆): δ 12.00(bs, 1H), 8.67 (s, 1H), 6.45 (bs, 1H), 4.59 (s, 2H), 3.06 (m, 2H), 2.83(m, 2H), 2.34 (m, 1H), 2.19 (s, 3H), 1.96 (m, 2H), 1.65 (m, 4H), 1.62(s, 6H), 1.43 (m, 2H), 0.88 (t, 3H). A27M1B03 ¹H NMR (400 MHz, DMSO-d₆):δ 12.25 (bs, 1H), 9.05 (s, 1H), 7.45 (m, 1H), 7.33 (m, 1H), 7.13 (m,1H), 6.81 (m, 1H), 4.68 (s, 2H), 2.89 (m, 2H), 2.40 (m, 1H), 2.26 (s,3H), 2.1 (m, 2H), 1.65 (m, 10H). A28M1B03.HCl ¹H NMR (400 MHz, DMSO-d₆):δ 12.13 (bs, 1H), 9.05 (bs, 1H), 4.64 (s, 2H), 3.5-3.2 (m, 8H), 2.75 (m,4H), 1.94 (m, 2H), 1.82 (m, 2H), 1.63 (m, 12H). A30M01B03 ¹H NMR (400MHz, DMSO-d₆): δ 12.48 (bs, 1H), 10.93 (bs, 1H), 8.0 (m, 2H), 7.61 (m,1H), 7.51 (m, 2H), 4.76 (bs, 2H), 2.86 (m, 2H), 2.38 (m, 1H), 2.23 (bs,3H), 2.03 (m, 2H), 1.67 (m, 10H). A01M1B04.HCl ¹H NMR (400 MHz,DMSO-d₆): δ 1.24 (t, J = 7.32 Hz, 3H) 1.69 (s, 6H) 1.98 (m, 4H) 2.78 (m,1H) 3.09 (dd, J = 7.32, 5.00 Hz, 4H) 3.50 (d, J = 11.71 Hz, 2H) 4.80 (s,2H) 7.36 (t, J = 8.78 Hz, 2H) 8.09 (m, 2H) 9.30 (s, 1H) 11.01 (s, 1H)12.56 (s, 1H). A03M1B04.HCl ¹H NMR (400 MHz, DMSO-d₆): δ 1.24 (t, J =7.32 Hz, 3H) 1.69 (s, 6H) 1.91 (m, 4H) 2.77 (m, 1H) 3.31 (m, 6H) 4.80(s, 2H) 7.61 (m, 1H) 7.91 (m, 1H) 8.07 (m, 1H) 9.24 (s, 1H) 11.11 (s,1H) 12.59 (s, 1H). A12M01B04.HCl ¹H NMR (400 MHz, DMSO-d₆): δ 0.92 (d, J= 6.58 Hz, 6H) 1.24 (t, J = 7.26 Hz, 3H) 1.65 (s, 6H) 1.88 (m, 4H) 2.06(m, 1H) 2.17 (d, J = 7.07 Hz, 2H) 2.70 (m, 1H) 3.23 (m, 6H) 4.72 (s, 2H)9.32 (s, 1H) 10.41 (s, 1H) 12.34 (s, 1H). A13M01B04.HCl ¹H NMR (400 MHz,DMSO-d₆): δ 1.25 (t, J = 7.32 Hz, 3H) 1.65 (s, 6H) 2.03 (m, 10H) 2.77(m, 1H) 3.28 (m, 7H) 4.75 (s, 2H) 9.31 (s, 1H) 10.30 (s, 1H) 12.35 (s,1H). A27M01B04.HCl ¹H NMR (400 MHz, DMSO-d₆): δ 1.24 (t, J = 7.32 Hz,3H) 1.66 (s, 6H) 1.89 (m, 4H) 2.75 (s, 1H) 3.18 (m, 6H) 4.73 (s, 2H)6.80 (m, 1H) 7.08 (ddd, J = 8.17, 1.95, 0.73 Hz, 1H) 7.32 (td, J = 8.17,6.95 Hz, 1H) 7.52 (dt, J = 11.89, 2.35 Hz, 1H) 9.10 (s, 1H) 9.22 (s, 1H)9.27 (s, 1H) 12.24 (s, 1H) A01M1B05 ¹H NMR (400 MHz, DMSO-d₆): δ 12.48(bs, 1H), 10.97 (s, 1H), 8.09 (m, 2H), 7.35 (m, 2H), 4.75 (s, 2H), 3.00(m, 2H), 2.44 (m, 1H), 2.24 (m, 2H), 1.8-1.5 (m, 5H), 1.67 (s, 6H), 0.38(m, 4H). A03M1B05.HCl ¹H NMR (400 MHz, DMSO-d₆): δ 0.82 (m, 2H) 0.99 (s,2H) 1.68 (s, 6H) 1.91 (m, 4H) 2.79 (m, 1H) 3.38 (m, 5H) 4.81 (s, 2H)7.62 (m, 1H) 7.92 (ddd, J = 8.72, 4.27, 1.40 Hz, 1H) 8.08 (ddd, J =11.52, 7.80, 2.13 Hz, 1H) 9.14 (s, 1H) 11.12 (s, 1H) 12.57 (s, 1H)A12M1B05.HCl ¹H NMR (400 MHz, DMSO-d₆): δ 0.82 (m, 2H) 0.93 (d, J = 6.58Hz, 6H) 1.00 (s, 2H) 1.65 (s, 6H) 1.90 (m, 4H) 2.06 (m, 1H) 2.17 (d, J =7.07 Hz, 2H) 2.76 (m, 1H) 3.36 (m, 5H) 4.73 (s, 2H) 9.20 (s, 1H) 10.41(s, 1H) 12.35 (s, 1H) A13M1B05.HCl ¹H NMR (400 MHz, DMSO-d₆): δ 0.82 (m,2H) 1.01 (s, 2H) 1.65 (s, 6H) 2.01 (m, 10H) 2.78 (m, 1H) 3.33 (m, 6H)4.77 (s, 2H) 9.23 (s, 1H) 10.30 (s, 1H) 12.25 (s, 1H) A27M1B05.HCl ¹HNMR (400 MHz, DMSO-d₆): δ 0.82 (q, J = 6.87 Hz, 2H) 1.00 (m, 2H) 1.66(s, 6H) 1.88 (m, 4H) 2.77 (m, 1H) 3.40 (m, 5H) 4.75 (s, 2H) 6.81 (m, 1H)7.09 (ddd, J = 8.11, 1.95, 0.79 Hz, 1H) 7.32 (td, J = 8.20, 7.01 Hz, 1H)7.52 (dt, J = 11.77, 2.23 Hz, 1H) 9.10 (s, 1H) 9.17 (m, 1H) 9.21 (s, 1H)12.99 (s, 1H) A01M1B06.HCl ¹H NMR (400 MHz, DMSO-d₆): δ 1.68 (s, 6H)1.80 (m, 4H) 2.81 (m, 1H) 3.01 (m, 2H) 3.38 (m, 2H) 4.78 (s, 2H) 7.36(t, J = 8.84 Hz, 2H) 8.09 (dd, J = 8.96, 5.43 Hz, 2H) 8.35 (m, 1H) 8.62(d, J = 9.88 Hz, 1H) 11.00 (s, 1H) 12.52 (s, 1H) A03M1B06.HCl ¹H NMR(400 MHz, DMSO-d₆): δ 1.68 (s, 6H) 1.83 (m, 4H) 2.80 (m, 1H) 3.00 (m,2H) 3.37 (m, 2H) 4.78 (s, 2H) 7.61 (m, 1H) 7.92 (m, 1H) 8.07 (ddd, J =11.49, 7.83, 2.13 Hz, 1H) 8.45 (m, 2H) 11.11 (s, 1H) 12.57 (s, 1H)A04M1B07 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.81 (s, 6H) 2.21 (s, 3H) 4.51(s, 2H) 6.96 (d, J = 4.88 Hz, 1H) 7.16 (t, J = 7.68 Hz, 1H) 7.35 (t, J =10.97 Hz, 1H) 7.54 (d, J = 5.00 Hz, 1H) 7.69 (m, 1H) 10.88 (s, 1H) 12.56(s, 1H) A12M1B07 ¹H NMR (400 MHz, DMSO-d₆): δ 12.37 (bs, 1H), 10.35 (s,1H), 7.54 (d, 1H, J = 5.0 Hz), 6.96 (d, 1H, J = 5.0 Hz), 4.42 (s, 2H),2.20 (s, 3H), 2.10 (d, 2H, J = 7.19 Hz), 1.98 (m, 1H), 1.77 (s, 3H),0.87 (d, 6H, J = 6.47 Hz). A13M1B07 ¹H NMR (400 MHz, DMSO-d₆): δ ppm1.74 (m, 1H) 1.77 (s, 6H) 1.88 (m, 1H) 2.02 (m, 2H) 2.14 (m, 2H) 2.20(s, 3H) 3.18 (m, 1H) 4.44 (s, 2H) 6.97 (d, J = 5.00 Hz, 1H) 7.55 (d, J =4.88 Hz, 1H) 10.25 (s, 1H) 12.36 (s, 1H) A14M1B07 ¹H NMR (400 MHz,DMSO-d₆): δ ppm 0.72 (m, 4H) 1.77 (s, 7H) 2.18 (s, 3H) 4.39 (s, 2H) 6.95(d, J = 5.00 Hz, 1H) 7.54 (d, J = 5.00 Hz, 1H) 10.69 (s, 1H) 12.37 (s,1H) A21M1B07 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.82 (s, 6H) 2.23 (s, 3H)4.53 (s, 2H) 6.61 (s, 1H) 6.98 (d, J = 5.00 Hz, 1H) 7.56 (d, J = 4.88Hz, 1H) 7.82 (s, 1H) 7.96 (m, 2H) 8.10 (d, J = 7.44 Hz, 2H) 8.64 (d, J =2.44 Hz, 1H) 10.98 (s, 1H) 12.57 (s, 1H) A23M1B07 ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.83 (s, 6H) 2.23 (s, 3H) 4.57 (s, 2H) 6.98 (d, J = 5.00Hz, 1H) 7.56 (d, J = 4.88 Hz, 1H) 7.63 (m, 2H) 8.01 (m, 4H) 8.63 (m, 1H)11.07 (s, 1H) 12.58 (s, 1H) A25M1B07 ¹H NMR (400 MHz, DMSO-d₆): δ ppm1.76 (s, 6H) 2.19 (s, 3H) 4.26 (d, J = 5.85 Hz, 2H) 4.36 (s, 2H) 6.86(s, 1H) 6.95 (d, J = 4.88 Hz, 1H) 7.22 (s, 3H) 7.32 (m, 2H) 7.53 (d, J =4.88 Hz, 1H) 8.82 (s, 1H) 12.14 (s, 1H) A27M1B07 ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.79 (s, 6H) 2.21 (s, 3H) 4.44 (s, 2H) 6.78 (m, 1H) 6.97(d, J = 4.88 Hz, 1H) 7.07 (m, 1H) 7.29 (m, 1H) 7.35 (m, 1H) 7.55 (d, J =5.00 Hz, 1H) 9.04 (s, 1H) 12.32 (s, 1H) A30M1B07 ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.81 (s, 6H) 2.22 (s, 3H) 4.52 (s, 2H) 6.97 (d, J = 5.00Hz, 1H) 7.48 (m, 2H) 7.56 (m, 1H) 7.56 (d, J = 5.00 Hz, 1H) 7.95 (d, J =7.32 Hz, 2H) 10.92 (s, 1H) 12.55 (s, 1H) A48M1B07 ¹H NMR (400 MHz,DMSO-d₆): δ ppm 1.73 (s, 6H) 2.13 (s, 3H) 3.71 (s, 2H) 4.35 (s, 2H) 6.89(d, J = 4.88 Hz, 1H) 7.40 (dd, J = 8.47, 1.65 Hz, 1H) 7.47 (m, 3H) 7.74(s, 1H) 7.84 (m, 3H) 10.74 (s, 1H) 12.40 (s, 1H) A53M1B07 ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.34 (m, 1H) 1.50 (m, 1H) 1.72 (m, 2H) 1.77 (s, 6H)1.98 (s, 3H) 2.19 (s, 3H) 2.55 (m, 2H) 3.00 (m, 1H) 3.81 (d, J = 12.56Hz, 1H) 4.35 (d, J = 12.07 Hz, 1H) 4.42 (s, 2H) 6.96 (d, J = 5.00 Hz,1H) 7.54 (d, J = 4.88 Hz, 1H) 10.45 (s, 1H) 12.40 (s, 1H) A54M1B07 ¹HNMR (400 MHz, DMSO-d₆): δ ppm 1.82 (s, 6H) 2.22 (s, 3H) 4.53 (s, 2H)6.97 (d, J = 5.00 Hz, 1H) 7.56 (d, J = 5.00 Hz, 1H) 7.72 (m, 1H) 7.91(m, 1H) 8.24 (m, 2H) 11.24 (s, 1H) 12.62 (s, 1H) A31M01B19.HCl ¹H NMR(400 MHz, DMSO-d₆): δ 1.80 (s, 6H) 2.07 (m, 4H) 2.81 (m, 3H) 3.14 (m,4H) 4.75 (m, 1H) 4.99 (s, 2H) 7.13 (m, 2H) 7.20 (dd, J = 4.94, 3.84 Hz,1H) 7.63 (dd, J = 3.72, 0.79 Hz, 1H) 7.80 (d, J = 5.00 Hz, 1H) 8.02 (m,2H) 10.07 (m, 1H) 10.86 (s, 1H) 11.99 (s, 1H) A31M1B20.HCl ¹H NMR (400MHz, DMSO-d₆): (mixture of two conformers) δ ppm 1.63 (m, 8H) 1.67 (s,12H) 1.86 (m, 2H) 2.10 (m, 4H) 2.28 (d, J = 14.0 Hz, 2H) 2.68 (m, 2H)2.79 (d, J = 5.0 Hz, 3H) 2.81 (d, J = 5.0 Hz, 3H)) 3.1-3.3 (m, 4H) 3.46(m, 2H) 3.52 (d, J = 14.0 Hz, 2H) 3.90 (m, 8H) 4.68 (m, 1H) 4.76 (m, 4H)4.89 (m, 1H) 7.11 (d, J = 8.9 Hz, 2H) 7.14 (d, J = 8.9 Hz, 2H) 8.01 (d,J = 8.9 Hz, 2H) 8.03 (d, J = 8.9 Hz, 2H) 10.02 (bs, 2H) 10.81 (bs, 2H)A33M1B20.HCl ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.65 (m, 4H) 1.68 (s, 6H)2.70 (m, 1H) 2.81 (s, 3H) 2.9-3-8 (bs, 8H) 3.90 (m, 4H) 4.06 (bs, 2H)4.77 (s, 2H) 7.62 (bs, 2H) 8.07 (d, J = 7.8 Hz, 2H) 10.60 (bs, 1H) 11.01(s, 1H) A12M1B44 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.14 (m, 2H) 0.46 (m,2H) 0.91 (d, J = 6.58 Hz, 6H) 1.01 (m, 1H) 1.66 (s, 6H) 2.05 (m, 1H)2.16 (d, J = 7.07 Hz, 2H) 2.24 (d, J = 6.58 Hz, 2H) 4.54 (s, 2H) 10.35(s, 1H) 12.27 (s, 1H) A13M1B44 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.15 (m,2H) 0.47 (m, 2H) 1.01 (m, 1H) 1.66 (s, 6H) 1.80 (m, 1H) 1.92 (m, 1H)2.08 (m, 2H) 2.17 (m, 2H) 2.26 (d, J = 6.46 Hz, 2H) 3.25 (m, 1H) 4.58(s, 2H) 10.25 (s, 1H) 12.26 (s, 1H) A14M1B44 ¹H NMR (400 MHz, DMSO-d₆):δ ppm 0.13 (m, 2H) 0.44 (m, 2H) 0.76 (m, 4H) 0.98 (m, 1H) 1.65 (s, 6H)1.81 (m, 1H) 2.22 (d, J = 6.58 Hz, 2H) 4.51 (s, 2H) 10.69 (s, 1H) 12.27(s, 1H) A25M1B44 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.13 (m, 2H) 0.45 (m,2H) 0.99 (m, 1H) 1.65 (s, 6H) 2.23 (d, J = 6.46 Hz, 2H) 4.31 (d, J =5.85 Hz, 2H) 4.49 (s, 2H) 6.89 (s, 1H) 7.25 (m, 1H) 7.28 (d, J = 7.07Hz, 2H) 7.34 (m, 2H) 8.83 (s, 1H) 12.04 (s, 1H) A26M1B44 ¹H NMR (400MHz, DMSO-d₆): δ ppm 0.14 (m, 2H) 0.47 (m, 2H) 0.87 (t, J = 7.44 Hz, 3H)1.00 (m, 1H) 1.43 (m, 2H) 1.64 (s, 6H) 2.23 (d, J = 6.58 Hz, 2H) 3.04(m, 2H) 4.48 (s, 2H) 6.43 (s, 1H) 8.65 (s, 1H) 12.00 (s, 1H) A30M1B44 ¹HNMR (400 MHz, DMSO-d₆): δ ppm 0.16 (m, 2H) 0.47 (m, 2H) 1.02 (m, 1H)1.70 (s, 6H) 2.28 (d, J = 6.58 Hz, 2H) 4.65 (s, 2H) 7.51 (m, 2H) 7.59(m, 1H) 8.01 (d, J = 7.44 Hz, 2H) 10.91 (s, 1H) 12.46 (s, 1H) A54M1B44¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.16 (m, 2H) 0.47 (m, 2H) 1.02 (m, 1H)1.70 (s, 6H) 2.28 (d, J = 6.58 Hz, 2H) 4.65 (s, 2H) 7.78 (m, 1H) 7.98(m, 1H) 8.35 (m, 2H) 11.25 (s, 1H) 12.53 (s, 1H) A04M1B45 ¹H NMR (400MHz, DMSO-d₆): δ ppm 0.60 (m, 1H) 0.97 (m, 1H) 1.12 (d, J = 5.97 Hz, 3H)1.19 (m, 1H) 1.51 (m, 1H) 1.66 (s, 6H) 4.86 (s, 2H) 7.20 (m, 1H) 7.40(m, 1H) 7.76 (m, 1H) 10.89 (s, 1H) 12.48 (s, 1H) A30M1B45 ¹H NMR (400MHz, DMSO-d₆): δ ppm 0.61 (m, 1H) 0.96 (m, 1H) 1.13 (d, J = 5.85 Hz, 3H)1.20 (m, 1H) 1.53 (m, 1H) 1.67 (s, 6H) 4.87 (s, 2H) 7.51 (m, 2H) 7.60(m, 1H) 8.02 (d, J = 7.07 Hz, 2H) 10.92 (s, 1H) 12.47 (s, 1H) A54M1B45¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.61 (m, 1H) 0.96 (m, 1H) 1.13 (d, J =5.85 Hz, 3H) 1.20 (m, 1H) 1.53 (m, 1H) 1.67 (s, 6H) 4.88 (s, 2H) 7.77(m, 1H) 7.96 (m, 1H) 8.31 (d, 1H) 8.39 (m, 1H) 11.26 (s, 1H) 12.54 (s,1H) A01M1B47 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.79 (s, 6H) 2.23 (s, 6H)3.52 (s, 2H) 4.43 (s, 2H) 7.26 (t, J = 8.78 Hz, 2H) 7.38 (m, 4H) 7.95(dd, J = 8.84, 5.55 Hz, 2H) 10.90 (s, 1H) 12.50 (s, 1H) A48M1B47 ¹H NMR(400 MHz, DMSO-d₆): δ ppm 1.79 (s, 6H) 2.14 (s, 6H) 3.41 (s, 2H) 3.67(s, 2H), 4.33 (s, 2H) 7.30 (m, 5H) 7.45 (m, 2H) 7.70 (m, 1H) 7.80 (m,3H) 10.70 (s, 1H) 12.37 (s, 1H) A48M1B48 ¹H NMR (400 MHz, DMSO-d₆): δppm 1.76 (s, 6H) 2.18 (s, 3H) 2.35 (m, 8H), 3.45 (s, 2H) 3.68 (s, 2H),4.34 (s, 2H) 7.30 (m, 5H) 7.47 (m, 2H) 7.70 (m, 1H) 7.81 (m, 3H) 10.70(s, 1H) 12.37 (s, 1H) A01M1B50 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.87 (t,J = 7.44 Hz, 3H) 1.49 (m, 2H) 1.68 (s, 6H) 2.27 (t, J = 7.38 Hz, 2H)4.64 (s, 2H) 7.30 (m, 2H) 8.04 (m, 2H) 10.92 (s, 1H) 12.43 (s, 1H)A04M1B50 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.93 (t, J = 7.44 Hz, 3H) 1.56(m, 2H) 1.68 (s, 6H) 2.28 (t, J = 7.38 Hz, 2H) 4.68 (s, 2H) 7.22 (m, 1H)7.40 (m, 1H) 7.75 (m, 1H) 10.88 (s, 1H) 12.47 (s, 1H) A13M1B50 ¹H NMR(400 MHz, DMSO-d₆): δ ppm 0.93 (t, J = 7.38 Hz, 3H) 1.55 (m, 2H) 1.64(s, 6H) 1.80 (m, 1H) 1.93 (m, 1H) 2.07 (m, 2H) 2.18 (m, 2H) 2.27 (t, J =7.38 Hz, 2H) 3.23 (m, 1H) 4.61 (s, 2H) 10.24 (s, 1H) 12.27 (s, 1H)A14M1B50 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.78 (d, J = 1.95 Hz, 4H) 0.91(t, J = 7.38 Hz, 3H) 1.52 (m, 2H) 1.64 (s, 6H) 1.82 (m, 1H) 2.24 (t, J =7.38 Hz, 2H) 4.55 (s, 2H) 10.70 (s, 1H) 12.27 (s, 1H) A30M1B50 ¹H NMR(400 MHz, DMSO-d₆): δ ppm 0.94 (t, J = 7.44 Hz, 3H) 1.57 (m, 2H) 1.69(s, 6H) 2.30 (t, J = 7.38 Hz, 2H) 4.68 (s, 2H) 7.52 (m, 2H) 7.60 (m, 1H)8.01 (d, J = 7.80 Hz, 2H) 10.92 (s, 1H) 12.46 (s, 1H) A54M1B50 ¹H NMR(400 MHz, DMSO-d₆): δ ppm 0.94 (t, J = 7.44 Hz, 3H) 1.57 (m, 2H) 1.69(s, 6H) 2.29 (t, J = 7.38 Hz, 2H) 4.70 (s, 2H) 8.31 (m, 4H) 11.25 (s,1H) 12.53 (s, 1H) A04M1B51 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.68 (s, 6H)2.03 (m, 2H) 3.27 (m, 1H) 3.73 (m, 3H) 3.93 (t, J = 8.11 Hz, 1H) 4.76(m, 2H) 7.21 (m, 1H) 7.39 (m, 1H) 7.74 (m, 1H) 10.90 (s, 1H) 12.49 (s,1H) A12M1B51 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.92 (d, J = 6.58 Hz, 6H)1.65 (s, 6H) 2.03 (m, 3H) 2.17 (d, J = 7.07 Hz, 2H) 3.21 (m, 1H) 3.73(m, 3H) 3.91 (t, J = 8.11 Hz, 1H) 4.66 (m, 2H) 10.38 (s, 1H) 12.30 (s,1H) A13M1B51 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.65 (s, 6H) 1.80 (m, 1H)1.96 (m, 3H) 2.07 (m, 2H) 2.19 (m, 2H) 3.26 (m, 2H) 3.74 (m, 3H) 3.92(t, J = 8.11 Hz, 1H) 4.70 (m, 2H) 10.27 (s, 1H) 12.29 (s, 1H) A14M1B51¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.78 (m, 4H) 1.64 (s, 6H) 1.83 (m, 1H)2.01 (m, 2H) 3.20 (m, 1H) 3.72 (m, 3H) 3.90 (t, J = 8.05 Hz, 1H) 4.64(m, 2H) 10.71 (s, 1H) 12.29 (s, 1H) A01M1B52 ¹H NMR (400 MHz, DMSO-d₆):δ ppm 1.79 (s, 6H) 4.43 (s, 2H) 7.2-7.95 (m, 9H) 10.90 (s, 1H) 12.50 (s,1H) A01M1B53 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.82 (s, 6H) 4.43 (s, 2H)7.15 (m, H) 7.27 (m, H) 7.34 (m, H) 7.58 (m, H) 7.68 (m, H) 10.93 (s,1H) 12.62 (s, 1H) A04M1B53 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.82 (s, 6H)4.43 (s, 2H) 7.15 (m, 1H) 7.27 (m, 2H) 7.34 (m, 1H) 7.58 (m, 1H) 7.68(m, 1H) 10.93 (s, 1H) 12.62 (s, 1H) A48M1B53 ¹H NMR (400 MHz, DMSO-d₆):δ ppm 1.73 (s, 6H) 3.69 (s, 2H) 4.27 (s, 2H) 7.18 (m, 2H) 7.38 (m, 1H)7.45 (m, 3H) 7.71 (m, 1H) 7.80 (m, 3H) 10.76 (s, 1H) 12.45 (s, 1H)A54M1B53 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.83 (s, 6H) 4.46 (s, 2H) 7.28(m, 2H) 7.59 (m, 1H) 7.71 (m, 1H) 7.92 (m, 1H) 8.21 (m, 1H) 8.29 (m, 1H)11.26 (s, 1H) 12.68 (s, 1H) A01M1B54 ¹H NMR (400 MHz, DMSO-d₆): δ ppm1.81 (s, 6H) 4.43 (s, 2H) 7.24 (m, 2H) 7.42 (m, 2H) 7.63 (d, J = 8.26Hz, 2H) 7.87 (d, J = 8.26 Hz, 2H) 7.95 (m, 2H) 10.93 (s, 1H) 12.62 (s,1H) A48M1B54 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.77 (s, 6H) 3.69 (s, 2H)4.33 (s, 2H) 7.32-7.89 (m, 13H) 10.75 (s, 1H) 12.41 (s, 1H) A01M2B03 ¹HNMR (400 MHz, DMSO-d₆): δ 12.20 (bs, 1H), 11.00 (s, 1H), 8.10 (m, 2H),7.36 (m, 2H), 4.91 (s, 2H), 2.84 (m, 2H), 2.4 (m, 1H), 2.23 (m, 5H), 2.0(m, 2H), 1.65 (m, 4H), 0.89 (m, 2H). A02M2B03 ¹H NMR (400 MHz, DMSO-d₆):δ 12.28 (bs, 1H), 11.08 (s, 1H), 7.88 (m, 2H), 7.51 (m, 2H), 4.92 (s,2H), 2.84 (m, 2H), 2.41 (m, 1H), 2.25 (m, 5H), 2.05 (m, 2H), 1.68 (m,4H), 0.91 (m, 2H). A04M2B03 ¹H NMR (400 MHz, DMSO-d₆): δ 12.24 (bs, 1H),10.91 (s, 1H), 7.75 (m, 1H), 7.41 (m, 1H), 7.22 (m, 1H), 4.91 (s, 2H),2.79 (m, 2H), 2.34 (m, 1H), 2.24 (m, 2H), 2.16 (s, 3H), 1.91 (m, 2H),1.65 (m, 4H), 0.89 (m, 2H). A05M2B03 ¹H NMR (400 MHz, DMSO-d₆): δ 12.31(bs, 1H), 11.16 (s, 1H), 7.75 (m, 2H), 7.51 (m, 1H), 4.91 (s, 2H), 2.79(m, 2H), 2.35 (m, 1H), 2.25 (m, 2H), 2.17 (s, 3H), 1.90 (m, 2H), 1.65(m, 4H), 0.90 (m, 2H). A06M2B03 ¹H NMR (400 MHz, DMSO-d₆): δ 12.45 (bs,1H), 11.06 (s, 1H), 8.03 (m, 2H), 7.61 (m, 2H), 4.91 (s, 2H), 2.84 (m,2H), 2.41 (m, 1H), 2.21 (m, 5H), 2.0 (m, 2H), 1.65 (m, 4H), 0.89 (m,2H). A07M2B03 ¹H NMR (400 MHz, DMSO-d₆): δ 12.30 (bs, 1H), 11.25 (s,1H), 8.20 (m, 2H), 7.92 (m, 2H), 4.94 (s, 2H), 2.95 (m, 2H), 2.45 (m,1H), 2.27 (m, 5H), 2.2 (m, 2H), 1.73 (m, 4H), 0.91 (m, 2H). A10M2B03 ¹HNMR (400 MHz, DMSO-d₆): δ 12.25 (bs, 1H), 11.04 (s, 1H), 8.15 (m, 1H),7.87 (m, 1H), 7.22 (m, 1H), 4.89 (s, 2H), 2.82 (m, 2H), 2.37 (m, 1H),2.22 (m, 5H), 1.9 (m, 2H), 1.65 (m, 4H), 0.91 (m, 2H). A11M2B03 ¹H NMR(400 MHz, DMSO-d₆): δ 12.22 (bs, 1H), 10.81 (s, 1H), 8.45 (m, 1H), 7.69(m, 2H), 4.90 (s, 2H), 2.82 (m, 2H), 2.37 (m, 1H), 2.24 (m, 2H), 2.18(m, 3H), 1.93 (m, 2H), 1.66 (m, 4H), 0.89 (m, 2H). A12M2B03 ¹H NMR (400MHz, DMSO-d₆): δ 12.06 (bs, 1H), 10.04 (s, 1H), 4.82 (s, 2H), 2.85 (m,2H), 2.34 (m, 1H), 2.22 (m, 7H), 2.05 (m, 3H), 1.65 (m, 4H), 0.93 (d,6H, J = 6.58 Hz), 0.85 (m, 2H). A13M2B03 ¹H NMR (400 MHz, DMSO-d₆): δ12.04 (bs, 1H), 10.08 (s, 1H), 4.85 (s, 2H), 3.25 (m, 1H), 2.85 (m, 2H),2.39 (m, 1H), 2.25-1.75 (m, 13H), 1.67 (m, 4H), 0.85 (m, 2H). A19M2B03¹H NMR (400 MHz, DMSO-d₆): δ 12.24 (bs, 1H), 10.84 (s, 1H), 7.94 (m,1H), 7.51 (m, 1H), 6.70 (m, 1H), 4.88 (s, 2H), 2.85 (m, 2H), 2.40 (m,1H), 2.22 (m, 5H), 2.01 (m, 2H), 1.67 (m, 4H), 0.89 (m, 2H). A38M2B03 ¹HNMR (400 MHz, DMSO-d₆): δ 12.21 (bs, 1H), 10.81 (s, 1H), 7.66 (m, 2H),7.08 (m, 1H), 4.92 (s, 2H), 3.86 (s, 6H), 2.81 (m, 2H), 2.38 (m, 1H),2.25 (m, 2H), 2.18 (s, 3H), 1.94 (m, 2H), 1.66 (m, 4H), 0.90 (m, 2H).A01M2B04 ¹H NMR (400 MHz, DMSO-d₆): δ 12.45 (bs, 1H), 11.00 (s, 1H),8.10 (m, 2H), 7.36 (m, 2H), 4.91 (s, 2H), 2.95 (m, 2H), 2.42 (m, 3H),2.24 (m, 2H), 1.95 (m, 2H), 1.7 (m, 4H), 1.02 (t, 3H), 0.89 (m, 2H).A02M2B04 ¹H NMR (400 MHz, DMSO-d₆): δ 12.27 (bs, 1H), 11.07 (s, 1H),7.85 (m, 2H), 7.68 (m, 1H), 7.45 (m, 1H), 4.91 (s, 2H), 2.90 (m, 2H),2.34 (m, 3H), 2.25 (m, 2H), 1.92 (m, 2H), 1.65 (m, 4H), 1.0 (t, 3H),0.90 (m, 2H). A04M2B04 ¹H NMR (400 MHz, DMSO-d₆): δ 12.23 (bs, 1H),10.91 (s, 1H), 7.78 (m, 1H), 7.41 (m, 1H), 7.22 (m, 1H), 4.91 (s, 2H),2.91 (m, 2H), 2.35 (m, 3H), 2.24 (m, 2H), 1.91 (m, 2H), 1.65 (m, 4H),1.00 (t, 3H), 0.89 (m, 2H). A05M2B04 ¹H NMR (400 MHz, DMSO-d₆): δ 12.31(bs, 1H), 11.16 (s, 1H), 7.75 (m, 2H), 7.54 (m, 1H), 4.92 (s, 2H), 2.92(m, 2H), 2.35 (m, 3H), 2.25 (m, 2H), 1.92 (m, 2H), 1.65 (m, 4H), 1.01(t, 3H), 0.90 (m, 2H). A06M2B04 ¹H NMR (400 MHz, DMSO-d₆): δ 12.25 (bs,1H), 11.05 (s, 1H), 8.03 (m, 2H), 7.6 (m, 2H), 4.91 (s, 2H), 2.90 (m,2H), 2.45-2.20 (m, 5H), 1.85 (m, 2H), 1.67 (m, 4H), 1.02 (t, 3H), 0.89(m, 2H). A07M2B04 ¹H NMR (400 MHz, DMSO-d₆): δ 12.31 (bs, 1H), 11.34 (s,1H), 8.20 (m, 2H), 7.91 (m, 2H), 4.95 (s, 2H), 3.15-1.5 (m, 13H), 1.06(t, 3H), 0.91 (m, 2H). A10M2B04 ¹H NMR (400 MHz, DMSO-d₆): δ 12.25 (bs,1H), 11.04 (s, 1H), 8.15 (m, 1H), 7.88 (m, 1H), 7.22 (m, 1H), 4.89 (s,2H), 2.92 (m, 2H), 2.45-2.20 (m, 5H), 1.9 (m, 2H), 1.65 (m, 4H), 1.01(t, 3H), 0.89 (m, 2H). A11M2B04 ¹H NMR (400 MHz, DMSO-d₆): δ 12.22 (bs,1H), 10.81 (s, 1H), 8.46 (m, 1H), 7.69 (m, 2H), 4.90 (s, 2H), 2.92 (m,2H), 2.34 (m, 3H), 2.25 (m, 2H), 1.92 (m, 2H), 1.65 (m, 4H), 1.01 (t,3H), 0.89 (m, 2H). A13M2B04 ¹H NMR (400 MHz, DMSO-d₆): δ 12.04 (bs, 1H),10.27 (s, 1H), 4.86 (s, 2H), 2.89 (m, 2H), 2.45-1.75 (m, 14H), 1.65 (m,4H), 1.00 (t, 3H), 0.85 (m, 2H). A14M2B04 ¹H NMR (400 MHz, DMSO-d₆): δ12.05 (bs, 1H), 10.71 (s, 1H), 4.79 (s, 2H), 2.88 (m, 2H), 2.31 (m, 3H),2.21 (m, 2H), 1.89 (m, 3H), 1.62 (m, 4H), 0.99 (t, 3H), 0.82 (m, 6H).A19M2B04 ¹H NMR (400 MHz, DMSO-d₆): δ 12.24 (bs, 1H), 10.84 (s, 1H),7.94 (m, 1H), 7.51 (m, 1H), 6.71 (m, 1H), 4.88 (s, 2H), 2.97 (m, 2H),2.40 (m, 3H), 2.24 (m, 2H), 2.01 (m, 2H), 1.68 (m, 4H), 1.02 (t, 3H),0.89 (m, 2H). A38M2B04 ¹H NMR (400 MHz, DMSO-d₆): δ 12.20 (bs, 1H),10.81 (s, 1H), 7.66 (m, 2H), 7.08 (m, 1H), 4.92 (s, 2H), 3.86 (s, 6H),2.92 (m, 2H), 2.45-2.20 (m, 5H), 1.84 (m, 2H), 1.66 (m, 4H), 1.01 (t,3H), 0.89 (m, 2H). A01M2B05 ¹H NMR (400 MHz, DMSO-d₆): δ 12.25 (bs, 1H),11.00 (s, 1H), 8.11 (m, 2H), 7.36 (m, 2H), 4.92 (s, 2H), 3.00 (m, 2H),2.44 (m, 1H), 2.24 (m, 4H), 1.6 (m, 5H), 0.89 (m, 2H), 0.38 (m, 4H).A06M2B05 ¹H NMR (400 MHz, DMSO-d₆): δ 12.3 (bs, 1H), 11.06 (s, 1H), 8.05(m, 2H), 7.6 (m, 2H), 4.92 (s, 2H), 3.00 (m, 2H), 2.44 (m, 1H), 2.24 (m,4H), 1.62 (m, 5H), 0.89 (m, 2H), 0.39 (m, 4H). A07M2B05 ¹H NMR (400 MHz,DMSO-d₆): δ 12.3 (bs, 1H), 11.24 (s, 1H), 8.21 (m, 2H), 7.9 (m, 2H),4.94 (s, 2H), 2.99 (m, 2H), 2.44 (m, 1H), 2.25 (m, 4H), 1.59 (m, 5H),0.89 (m, 2H), 0.37 (m, 4H). A01M2B06.HCl ¹H NMR (400 MHz, DMSO-d₆): δ0.92 (m, 2H), 1.78 (m, 4H) 2.24 (m, 2H), 2.81 (m, 1H) 3.01 (m, 2H) 3.38(m, 2H) 4.95 (s, 2H) 7.37 (t, J = 8.84 Hz, 2H) 8.10 (dd, J = 8.96, 5.43Hz, 2H) 8.35 (m, 1H) 8.65 (d, J = 9.88 Hz, 1H) 11.00 (s, 1H) 12.52 (s,1H) A01M2B47 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.01 (m, 2H) 2.18 (s, 6H)2.36 (m, 2H) 3.46 (s, 2H) 4.62 (s, 2H) 7.28 (m, 2H) 7.36 (m, 2H) 7.41(m, 2H) 7.98 (m, 2H) 10.93 (s, 1H) 12.27 (s, 1H) A48M2B53 ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.13 (m, 2H) 2.29 (m, 2H) 3.72 (s, 2H) 4.43 (s, 2H)7.18 (m, 2H) 7.38 (m, 1H) 7.45 (m, 3H) 7.71 (m, 1H) 7.80 (m, 3H) 10.79(s, 1H) 12.23 (s, 1H)

EXAMPLE 19N-{6,6-dimethyl-5-[(4-methylpiperazin-1-yl)carbonyl]-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-fluorobenzamide

To a solution of triphosgene (195 mg, 0.65 mmol, 0.56 eq) in DCM (15 ml)was added a solution of ethyl3-[(4-fluorobenzoyl)amino]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylatehydrochloride (442 mg, 1.15 mmol) in DCM (30 ml) followed byN,N-diisopropylethylamine (760 μl, 4.31 mmol, 3.75 eq). After 3 hours, asolution of N-methylpiperazine (195 μl, 1.72 mmol, 1.5 eq) anddiisopropylethylamine (300 μl, 1.72 mmol, 1.5 eq) in DCM (8 ml) wasadded. The reaction was stirred overnight at room temperature (TLC:CH₂Cl₂/MeOH 90/10). The solution was washed with brine, the organicphase was dried over sodium sulfate and concentrated. The residue wasdissolved in methanol (16 ml), treated with TEA (1.6 ml, 11.5 mmol, 10eq) and stirred overnight at room temperature. (TLC: CH₂Cl₂/MeOH 90/10).After evaporation, the solid was purified by flash chromatography(eluent: CH₂Cl₂/MeOH 90/10). The solid was treated with diisopropyletherand filtered to afford 0.294 g of the title compound in 64% yield.

ESI MS: m/z 401 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 12.39 (bs, 1H), 10.39 (s, 1H), 8.04 (m, 2H,Ar), 7.31 (m, 2H), 4.53 (bs, 2H), 3.04 (m, 4H), 2.40 (m, 4H), 2.22 (bs,3H), 1.60 (bs, 6H).

By working in an analogous manner the following compounds were prepared:

N-[5-[(4-methylpiperazin-1-yl)carbonyl]-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-6-spirocyclopropan-3-yl]-4-fluorobenzamide

ESI MS: m/z 399 (MH+);

¹H NMR (400 MHz, DMSO-d₆): δ 12.19 (bs, 1H), 10.95 (s, 1H), 8.09 (m,2H), 7.35 (m, 2H), 4.70 (bs, 2H), 3.18 (m, 4H), 2.34 (m, 7H), 1.92 (m,2H), 0.97 (m, 2H).

EXAMPLE 204-Chloro-N-[6,6-dimethyl-5-(4-pyrrolidin-1-ylmethyl-piperidine-1-carbonyl)-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzamide,hydrochloride

A mixture ofN-[5-(4-aminomethyl-piperidine-1-carbonyl)-6,6-dimethyl-2,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-chloro-benzamide(310 mg, 0.7 mmoles), 1,4-dibromobutane (92 μl, 0.7 mmoles) and NaHCO₃(600 mg, 7 mmoles) in absolute ethanol (15 ml) was heated at 150° C. for15 minutes in a microwave oven. After cooling, the solution wasevaporated. The residue was taken up with dichloromethane/MeOH (90:10)and water, the suspension obtained filtered and the organic layer wasevaporated to dryness. The residue was purified by flash chromatographywith dichloromethane/MeOH/30% NH₄OHaq (95/5/0.5). The product wasobtained in 20% yield (71 mg).

The compound was dissolved in methanol (3 ml), a solution of 4N HCl indioxane (40 μl, 0.16 mmoles) was added and then the solution wasevaporated. The solid obtained was triturated in ether to give the titlehydrochloride salt as a white powder.

ESI MS: m/z 485 (MH+);

¹H NMR (400 MHz, DMSO-D6) δ ppm 1.24 (m, 2 H) 1.63 (s, 6 H) 1.92 (m, 7H) 2.67 (t, J=11.83 Hz, 2 H) 3.01 (m, 2 H) 3.09 (t, J=6.46 Hz, 2 H) 3.47(m, 4 H) 4.56 (s, 2 H) 7.59 (d, J=8.54 Hz, 2 H) 8.01 (d, J=8.66 Hz, 2 H)9.49 (s, 1 H) 11.02 (s, 1 H) 12.50 (s, 1 H)

By working in analogous manner and by using the proper starting materialand any suitable reactant, as per the aforementioned process, additionalcompounds of formula (Ia) and (Ib) were also prepared, as reported inthe following table V.

TABLE V A03M1B08.HCl ¹H NMR (400 MHz, DMSO-d₆): δ 1.65 (d, J = 9.15 Hz,6H) 2.84 (d, J = 3.17 Hz, 3H) 3.06 (s, 4H) 3.58 (s, 4H) 4.62 (s, 2H)7.61 (m, 1H) 7.91 (m, 1H) 8.07 (m, 1H) 9.98 (s, 1H) 11.08 (s, 1H) 12.61(s, 1H) A04M1B08 ¹H NMR (400 MHz, DMSO-d₆): δ 12.44 (bs, 1H), 10.85 (s,1H), 7.74 (m, 1H), 7.18 (m, 1H), 7.20 (s, 1H), 4.59 (bs, 2H), 3.06 (m,4H), 2.38 (m, 4H), 2.22 (bs, 3H), 1.64 (bs, 6H). A06M1B08 ¹H NMR (400MHz, DMSO-d₆): δ 12.46 (bs, 1H), 10.99 (s, 1H), 8.01 (m, 2H), 7.59 (m,2H), 4.59 (bs, 2H), 3.07 (m, 4H), 2.40 (m, 4H), 2.25 (bs, 3H), 1.64 (bs,6H). A07M1B08 ¹H NMR (400 MHz, DMSO-d₆): δ 12.49 (bs, 1H), 11.16 (s,1H), 8.19 (d, 2H, J = 7.80 Hz), 7.88 (d, 2H, J = 7.80 Hz), 4.60 (s, 2H),3.06 (m, 4H), 2.38 (m, 4H), 2.22 (s, 3H), 1.64 (bs, 6H). A12M1B08 ¹H NMR(400 MHz, DMSO-d₆): δ 12.24 (bs, 1H), 10.32 (s, 1H), 4.47 (s, 2H), 3.03(m, 4H), 2.34 (m, 4H), 2.20 (s, 3H), 2.15 (d, 2H, J = 7.20 Hz), 2.05 (m,1H), 1.59 (s, 6H), 0.92 (d, 6H, J = 6.59 Hz). A13M1B08 ¹H NMR (400 MHz,DMSO-d₆): δ 12.23 (bs, 1H), 10.22 (s, 1H), 4.50 (bs, 2H), 3.32 (m, 1H),3.04 (m, 4H), 2.35 (m, 4H), 2.21 (s, 3H), 1.91-1.8 (m, 6H), 1.59 (bs,6H). A14M1B08 ¹H NMR (400 MHz, DMSO-d₆): δ 12.23 (bs, 1H), 10.66 (s,1H), 4.44 (bs, 2H), 3.02 (m, 4H), 2.33 (m, 4H), 2.19 (s, 3H), 1.82 (m,1H), 1.59 (bs, 6H), 0.78 (m, 4H). A16M1B08 ¹H NMR (400 MHz, DMSO-d₆): δ12.46 (bs, 1H), 11.04 (s, 1H), 8.12 (m, 2H), 7.51 (m, 2H), 4.57 (bs,2H), 3.06 (m, 4H), 2.36 (m, 4H), 2.20 (s, 3H), 1.64 (bs, 6H). A17M1B08¹H NMR (400 MHz, DMSO-d₆): δ 12.44 (bs, 1H), 10.94 (s, 1H), 7.78 (m,1H), 7.61 (bs, 1H), 7.51 (m, 1H), 7.45 (m, 2H), 7.20 (m, 2H), 7.09 (m,2H), 4.55 (bs, 2H), 3.06 (m, 4H), 2.40 (m, 4H), 2.24 (bs, 3H), 1.63 (bs,6H). A18M1B08 ¹H NMR (400 MHz, DMSO-d₆): δ 12.44 (bs, 1H), 10.99 (s,1H), 7.96 (m, 2H), 7.47-7.33 (m, 7H), 4.55 (bs, 2H), 3.03 (m, 4H), 2.52(m, 4H), 2.28 (bs, 3H), 1.63 (bs, 6H). A21M1B08 ¹H NMR (400 MHz,DMSO-d₆): δ 12.44 (bs, 1H), 10.95 (bs, 2H), 8.66 (m, 1H), 8.14 (m, 2H),8.00 (m, 2H), 7.83 (m, 1H), 6.82 (m, 1H), 4.59 (s, 2H), 3.06 (m, 4H),2.36 (m, 4H), 2.21 (s, 3H), 1.64 (bs, 6H). A22M1B08 ¹H NMR (400 MHz,DMSO-d₆): δ 12.41 (bs, 1H), 11.06 (bs, 1H), 8.50-7.60 (m, 7H), 4.64 (s,2H), 3.07 (m, 4H), 2.35 (m, 4H), 2.18 (s, 3H), 1.66 (bs, 6H). A23M1B08¹H NMR (400 MHz, DMSO-d₆): δ 12.45 (bs, 1H), 11.05 (bs, 1H), 8.66 (bs,1H), 7.07 (m, 4H), 7.65 (m, 2H), 4.62 (s, 2H), 3.07 (m, 4H), 2.37 (m,4H), 2.21 (s, 3H), 1.65 (bs, 6H). A24M1B08 ¹H NMR (400 MHz, DMSO-d₆): δ12.02 (bs, 1H), 8.80 (s, 1H), 7.19 (m, 4H), 6.90 (bs, 1H), 4.42 (s, 2H),4.31 (d, 2H J = 5.73 Hz), 3.02 (m, 4H), 2.34 (m, 4H), 2.30 (s, 3H), 2.20(s, 3H), 1.59 (s, 6H). A25M1B08 ¹H NMR (400 MHz, DMSO-d₆): δ 12.02 (bs,1H), 8.83 (s, 1H), 7.31 (m, 5H), 6.99 (bs, 1H), 4.42 (s, 2H), 4.33 (d,2H J = 5.85 Hz), 3.02 (m, 4H), 2.34 (m, 4H), 2.19 (s, 3H), 1.59 (s, 6H).A26M1B08 ¹H NMR (400 MHz, DMSO-d₆): δ 12.00 (bs, 1H), 8.65 (s, 1H), 6.54(m, 1H), 4.41 (s, 2H), 3.02 (m, 6H), 2.34 (m, 4H), 2.20 (s, 3H), 1.58(s, 6H), 1.43 (m, 2H), 0.88 (t, 3H). A27M1B08 ¹H NMR (400 MHz, DMSO-d₆):δ 12.22 (bs, 1H), 9.16 (s, 2H), 7.46 (m, 1H), 7.33 (m, 1H), 7.13 (m,1H), 6.80 (m, 1H), 6.99 (bs, 1H), 4.48 (s, 2H), 3.05 (m, 4H), 2.35 (m,4H), 2.20 (s, 3H), 1.61 (s, 6H). A01M1B09 ¹H NMR (400 MHz, DMSO-d₆): δ12.37 (bs, 1H), 10.88 (s, 1H), 8.04 (m, 2H), 7.31 (m, 2H), 4.51 (bs,2H), 2.97 (m, 4H), 1.59 (bs, 6H), 1.50 (m, 6H). A06M1B09 ¹H NMR (400MHz, DMSO-d₆): δ 12.44 (bs, 1H), 10.98 (s, 1H), 8.01 (d, 2H, J = 8.3Hz), 7.58 (d, 2H, J = 8.3 Hz), 4.57 (bs, 2H), 3.00 (m, 4H), 1.63 (bs,6H), 1.54 (m, 6H). A01M1B10 ¹H NMR (400 MHz, DMSO-d₆): δ 12.41 (bs, 1H),10.89 (s, 1H), 8.04 (m, 2H), 7.30 (m, 2H), 4.56 (bs, 2H), 3.59 (m, 4H),3.01 (m, 4H), 1.61 (bs, 6H). A01M1B11 ¹H NMR (400 MHz, DMSO-d₆): δ 12.52(bs, 1H), 10.91 (s, 1H), 8.07 (m, 2H), 7.35 (m, 2H), 4.54 (bs, 2H), 3.33(m, 2H), 2.63 (m, 2H), 1.63 (m, 8H), 1.49 (m, 1H), 1.15 (m, 2H), 0.94(d, 3H, J = 6.5 Hz). A13M1B11 ¹H NMR (400 MHz, DMSO-d₆): δ 12.23 (bs,1H), 10.19 (s, 1H), 4.50 (s, 2H), 3.33 (m, 3H), 2.62 (m, 2H), 2.4-1.4(m, 15H), 1.15 (m, 2H), 0.95 (d, 3H, J = 6.58 Hz). A14M1B11 ¹H NMR (400MHz, DMSO-d₆): δ 12.23 (bs, 1H), 10.63 (s, 1H), 4.43 (s, 2H), 3.33 (m,2H), 2.61 (m, 2H), 1.9-1.4 (m, 10H), 1.11 (m, 2H), 0.95 (d, 3H, J = 6.58Hz), 0.77 (m, 4H). A14M1B12 ¹H NMR (400 MHz, DMSO-d₆): δ 12.23 (bs, 1H),10.64 (s, 1H), 4.43 (s, 3H), 3.33 (m, 4H), 2.60 (m, 2H), 1.59 (m, 10H),1.11 (m, 2H), 0.78 (m, 4H). A01M1B13 ¹H NMR (400 MHz, DMSO-d₆): δ 12.42(bs, 1H), 10.91 (s, 1H), 8.08 (m, 2H), 7.33 (m, 2H), 4.56 (bs, 2H), 4.35(bs, 1H), 3.46 (m, 4H), 2.65 (m, 2H), 1.75-1.05 (m, 13H). A02M2B08 ¹HNMR (400 MHz, DMSO-d₆): δ 12.00 (bs, 1H), 11.02 (s, 1H), 7.86 (m, 2H),7.57 (m, 2H), 4.70 (bs, 2H), 3.14 (m, 4H), 2.40 (m, 4H), 2.25 (bs, 3H),1.91 (m, 2H), 0.97 (m, 2H). A04M2B08 ¹H NMR (400 MHz, DMSO-d₆): δ 12.16(bs, 1H), 10.84 (s, 1H), 7.76 (m, 3H), 4.69 (bs, 2H), 3.12 (m, 4H), 2.35(m, 4H), 2.21 (bs, 3H), 1.90 (m, 2H), 0.97 (m, 2H). A06M2B08 ¹H NMR (400MHz, DMSO-d₆): δ 12.20 (bs, 1H), 11.00 (s, 1H), 8.02 (m, 2H), 7.59 (m,2H), 4.70 (bs, 2H), 3.15 (m, 4H), 2.51 (m, 4H), 2.29 (bs, 3H), 1.92 (m,2H), 0.89 (m, 2H). A07M2B08 ¹H NMR (400 MHz, DMSO-d₆): δ 12.24 (bs, 1H),11.17 (s, 1H), 8.19 (m, 2H), 7.89 (m, 2H), 4.72 (bs, 2H), 3.14 (m, 4H),2.41 (m, 4H), 2.26 (bs, 3H), 1.92 (m, 2H), 0.98 (m, 2H). A10M2B08 ¹H NMR(400 MHz, DMSO-d₆): δ 12.18 (bs, 1H), 10.98 (s, 1H), 8.11 (m, 1H), 7.87(m, 1H), 7.21 (m, 1H), 4.66 (bs, 2H), 3.13 (m, 4H), 2.37 (m, 4H), 2.23(bs, 3H), 1.91 (m, 2H), 0.97 (m, 2H). A14M2B08 ¹H NMR (400 MHz,DMSO-d₆): δ 11.98 (bs, 1H), 10.66 (s, 1H), 4.56 (bs, 2H), 3.10 (m, 4H),2.34 (m, 4H), 2.21 (bs, 3H), 1.87 (m, 2H), 1.86 (m, 1H), 0.92 (m, 2H),0.82 (m, 4H). A17M2B08 ¹H NMR (400 MHz, DMSO-d₆): δ 12.17 (bs, 1H),10.95 (s, 1H), 7.79 (m, 1H), 7.62 (bs, 1H), 7.51 (m, 1H), 7.45 (m, 2H),7.27 (m, 1H), 7.20 (m, 1H), 7.09 (m, 2H), 4.66 (bs, 2H), 3.12 (m, 4H),2.35 (m, 4H), 2.21 (s, 3H), 1.90 (m, 2H), 0.98 (m, 2H). A18M2B08 ¹H NMR(400 MHz, DMSO-d₆): δ 12.17 (bs, 1H), 11.00 (s, 1H), 7.97 (bs, 1H), 7.94(m, 1H), 7.42 (m, 7H), 4.67 (bs, 2H), 3.11 (m, 4H), 2.32 (m, 4H), 2.20(s, 3H), 1.90 (m, 2H), 0.98 (m, 2H). A19M2B08 ¹H NMR (400 MHz, DMSO-d₆):δ 12.17 (bs, 1H), 10.77 (s, 1H), 7.92 (bs, 1H), 7.49 (m, 1H), 6.69 (m,1H), 4.66 (bs, 2H), 3.12 (m, 4H), 2.37 (m, 4H), 2.23 (s, 3H), 1.90 (m,2H), 0.96 (m, 2H). A01M2B09 ¹H NMR (400 MHz, DMSO-d₆): δ 12.13 (bs, 1H),10.93 (s, 1H), 8.09 (m, 2H), 7.36 (m, 2H), 4.65 (bs, 2H), 3.08 (m, 4H),1.87 (m, 2H), 1.53 (m, 6H), 0.96 (m, 2H). A01M2B10 ¹H NMR (400 MHz,DMSO-d₆): δ 12.10 (bs, 1H), 10.95 (s, 1H), 8.09 (m, 2H), 7.34 (m, 2H),4.70 (bs, 2H), 3.62 (m, 4H), 3.12 (m, 4H), 1.93 (m, 2H), 0.96 (m, 2H).A01M2B11 ¹H NMR (400 MHz, DMSO-d₆): δ 12.15 (bs, 1H), 10.93 (s, 1H),8.09 (m, 2H), 7.36 (m, 2H), 4.65 (bs, 2H), 3.54 (m, 2H), 2.65 (m, 2H),1.87 (m, 2H), 1.61 (m, 2H), 1.50 (m, 1H), 1.12 (m, 2H), 0.94 (m, 5H).A01M2B12 ¹H NMR (400 MHz, DMSO-d₆): δ 11.88 (bs, 1H), 10.93 (s, 1H),8.08 (m, 2H), 7.36 (m, 2H), 4.66 (bs, 2H), 3.54 (m, 2H), 3.45 (m, 3H),2.65 (m, 2H), 1.87 (m, 2H), 1.66 (m, 2H), 1.50 (m, 1H), 1.12 (m, 2H),0.94 (m, 2H). A01M2B13 ¹H NMR (400 MHz, DMSO-d₆): δ 11.33 (bs, 1H),10.93 (s, 1H), 8.08 (m, 2H), 7.36 (m, 2H), 4.65 (bs, 2H), 3.54 (m, 2H),3.45 (m, 3H), 2.65 (m, 2H), 1.87 (m, 2H), 1.66 (m, 2H), 1.50 (m, 1H),1.40 (m, 2H), 1.12 (m, 2H), 0.95 (m, 2H). A48M1B08 ¹H NMR (400 MHz,DMSO-d₆): δ 1.55 (s, 6H), 2.19 (s, 3H), 2.35 (m, 4H), 2.98 (m, 4H), 3.75(s, 2H), 4.44 (s, 2H), 7.5 (m, 3H), 7.75 (s, 1H), .7.85 (m, 3H), 10.7(bs, 1H), 12.5 (bs, 1H). A30M1B08 ¹H NMR (400 MHz, DMSO-d₆): δ 1.63 (s,6H), 2.20 (s, 3H), 2.36 (m, 4H), 3.06 (m, 4H), 4.57 (s, 2H), 7.51 (m,2H), 7.60 (m, 1H), 7.99 (m, 2H), 10.89 (bs, 1H), 12.42 (bs, 1H).A38M2B08 ¹H NMR (400 MHz, DMSO-d₆): δ 0.96 (m, 2H), 1.91 (bs, 2H), 2.23(bs, 3H), 2.37 (bs, 4H), 3.13 (bs, 4H), 3.86 (s, 6H), 4.69 (s, 2H), 7.07(s, 1H), 7.66 (bs, 2H), 10.76 (s, 1H), 12.14 (bs, 1H). A54M1B08 ¹H NMR(400 MHz, DMSO-d₆): δ 1.64 (s, 6H), 2.20 (s, 3H), 2.36 (m, 4H), 3.06 (m,4H), 4.59 (bs, 2H), 7.77 (m, 1H), 7.96 (m, 1H), 8.3 (m, 1H), 8.36 (s,1H), 11.23 (s, 1H), 12.50 (bs, 1H). A04M1B12 ¹H NMR (400 MHz, DMSO-d₆):δ 1.16 (m, 2H), 1.4-1.75 (m, 9H), 2.62 (m, 2H), 3.33 (m, 4H), 4.46 (t,1H), 4.56 (bs, 2H), 7.2 (m, 2H), 7.75 (m, 1H), 10.84 (s, 1H), 12.43 (s,1H). A01M1B12 ¹H NMR (400 MHz, DMSO-d₆): δ 1.17 (m, 2H), 1.51 (m, 1H),1.63 (s, 6H), 1.66 (m, 2H), 2.62 (m, 2H), 3.32 (m, 4H), 4.54 (bs, 2H),7.35 (m, 2H), 8.07 (m, 2H), 10.92 (s, 1H), 12.4 (bs, 1H). A48M1B13 ¹HNMR (400 MHz, DMSO-d₆): δ 12.25 (bs, 1H), 10.7 (s, 1H), 7.85 (m, 3H),7.8 (s, 1H), 7.45 (m, 3H), 4.4 (bs, 2H), 4.3 (t, 1H), 3.75 (s, 2H), 3.44(m, 4H), 2.65 (m, 2H), 1.70 (m, 2H), 1.67 (s, 6H), 1.52 (m, 1H), 1.39(m, 2H), 1.15 (m, 2H). A30M1B13 ¹H NMR (400 MHz, DMSO-d₆): δ 7.99 (m,2H), 7.59 (m, 1H), 7.51 (m, 2H), 4.56 (bs, 2H), 4.35 (t, 1H), 3.46 (m,4H), 2.97 (m, 2H), 1.45-1.95 (m, 11H), 1.17 (m, 2H). A23M1B13 ¹H NMR(400 MHz, DMSO-d₆): δ 12.45 (bs, 1H), 11.02 (s, 1H), 8.67 (s, 1H), 8.07(m, 4H), 7.65 (m, 2H), 4.61 (bs, 2H), 4.35 (t, 1H), 3.46 (m, 4H), 2.63(m, 2H), 1.45-1.85 (m, 8H), 1.52 (m, 1H), 1.42 (m, 2H), 1.18 (m, 2H).A14M1B13 ¹H NMR (400 MHz, DMSO-d₆): δ 12.23 (bs, 1H), 10.64 (s, 1H),4.42 (bs, 2H), 4.35 (t, 1H), 3.47 (m, 2H), 3.33 (m, 2H), 2.56 (m, 2H),1.82 (m, 1H), 1.65 (m, 2H), 1.59 (s, 6H), 1.52 (m, 1H), 1.4 (m, 2H),1.12 (m, 2H), 0.78 (m, 4H). A04M1B13 ¹H NMR (400 MHz, DMSO-d₆): δ 12.43(bs, 1H), 10.84 (s, 1H), 7.76 (m, 1H), 7.38 (m, 1H), 7.2 (m, 1H), 4.56(bs, 2H), 4.34 (t, 1H), 3.45 (m, 2H), 3.33 (m, 2H), 2.56 (m, 2H),1.75-1.55 (m, 8H), 1.53 (m, 1H), 1.40 (m, 2H), 1.15 (m, 2H). A16M1B13 ¹HNMR (400 MHz, DMSO-d₆): δ 12.45 (bs, 1H), 11.02 (s, 1H), 8.12 (m, 2H),7.51 (m, 2H), 4.56 (bs, 2H), 4.35 (t, 1H), 3.48-3.20 (m, 4H), 2.61 (m,2H), 1.72-1.09 (m, 13H). A22M1B13 ¹H NMR (400 MHz, DMSO-d₆): δ 12.40(bs, 1H), 11.02 (s, 1H), 7.3-8.4 (m, 7H), 4.65 (bs, 2H), 4.33 (t, 1H),3.44 (m, 4H), 2.65 (m, 2H), 1.70 (m, 2H), 1.67 (s, 6H), 1.52 (m, 1H),1.39 (m, 2H), 1.15 (m, 2H). A13M1B13 ¹H NMR (400 MHz, DMSO-d₆): δ 1.15(m, 2H) 1.40 (q, J = 6.54 Hz, 2H) 1.51 (m, 1H) 1.59 (s, 6H) 1.68 (m, 2H)1.79 (m, 1H) 1.91 (m, 1H) 2.07 (m, 2H) 2.17 (m, 2H) 2.61 (t, J = 12.13Hz, 2H) 3.24 (m, 1H) 3.39 (d, J = 14.75 Hz, 2H) 3.47 (m, 2H) 4.35 (m,1H) 4.49 (s, 2H) 10.19 (s, 1H) 12.22 (s, 1H) A21M1B13 ¹H NMR (400 MHz,DMSO-d₆): δ 1.16 (m, 2H) 1.40 (q, J = 6.71 Hz, 2H) 1.55 (m, 1H) 1.64 (s,6H) 1.69 (d, J = 12.80 Hz, 2H) 2.62 (m, 2H) 3.42 (d, J = 11.83 Hz, 2H)3.47 (m, 2H) 4.35 (t, J = 5.12 Hz, 1H) 4.58 (s, 2H) 6.62 (m, 1H) 7.83(d, J = 1.46 Hz, 1H) 7.99 (d, J = 9.39 Hz, 2H) 8.15 (d, J = 8.17 Hz, 2H)8.65 (d, J = 2.44 Hz, 1H) 10.94 (s, 1H) 12.43 (s, 1H) A25M1B13 ¹H NMR(400 MHz, DMSO-d₆): δ 12.02 (bs, 1H), 8.82 (bs, 1H), 7.3 (m, 5H), 7.0(bs, 1H), 4.40 (s, 2H), 4.33 (m, 3H), 3.45 (m, 2H), 3.33 (m, 2H), 2.59(m, 2H), 1.66 (m, 2H), 1.57 (m, 7H), 1.40 (m, 2H), 1.13 (m, 2H).A27M1B13 ¹H NMR (400 MHz, DMSO-d₆): δ 12.20 (bs, 1H), 9.02 (bs, 1H),7.45 (m, 1H), 7.31 (m, 1H), 7.12 (m, 1H), 6.81 (m, 1H), 4.47 (bs, 2H),4.34 (t, 1H), 3.46 (m, 2H), 3.32 (m, 2H), 2.62 (m, 2H), 1.66 (m, 2H),1.58 (m, 7H), 1.40 (m, 2H), 1.15 (m, 2H). A24M1B13 ¹H NMR (400 MHz,DMSO-d₆): δ 12.03 (bs, 1H), 8.79 (bs, 1H), 7.24 (m, 1H), 7.18 (m, 3H),6.92 (bs, 1H), 4.39 (bs, 2H), 4.35 (t, 1H), 4.31 (m, 2H), 3.46 (m, 2H),3.33 (m, 2H), 2.56 (m, 2H), 2.3 (s, 3H), 1.65 (m, 2H), 1.58 (m, 7H),1.40 (m, 2H), 1.13 (m, 2H). A26M1B13 ¹H NMR (400 MHz, DMSO-d₆): δ 11.99(bs, 1H), 8.66 (bs, 1H), 6.56 (bs, 1H), 4.38 (bs, 2H), 4.35 (t, 1H),3.46 (m, 2H), 3.32 (m, 2H), 3.05 (m, 2H), 2.56 (m, 2H), 1.66 (m, 2H),1.57 (m, 7H), 1.46 (m, 4H), 1.14 (m, 2H), 0.88 (t, 3H). A12M1B13 ¹H NMR(400 MHz, DMSO-d₆): δ ppm 0.92 (d, J = 6.46 Hz, 6H) 1.12 (m, 2H) 1.39(q, J = 6.58 Hz, 2H) 1.54 (m, 1H) 1.59 (s, 6H) 1.67 (d, J = 14.51 Hz,2H) 2.06 (m, 1H) 2.16 (d, J = 6.95 Hz, 2H) 2.60 (m, 2H) 3.38 (m, 2H)3.46 (m, 2H) 4.35 (t, J = 5.12 Hz, 1H) 4.46 (s, 2H) 10.30 (s, 1H) 12.23(s, 1H) A54M1B13 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.15 (m, 2H) 1.40 (q,J = 6.63 Hz, 2H) 1.53 (m, 1H) 1.64 (s, 6H) 1.68 (d, J = 12.93 Hz, 2H)2.62 (t, J = 11.89 Hz, 2H) 3.42 (d, J = 11.22 Hz, 2H) 3.46 (m, 2H) 4.35(t, J = 4.88 Hz, 1H) 4.57 (s, 2H) 7.77 (t, J = 8.72 Hz, 1H) 7.97 (d, J =6.10 Hz, 1H) 8.30 (d, J = 7.68 Hz, 1H) 8.36 (s, 1H) 11.21 (s, 1H) 12.49(s, 1H) A01M1B27 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.86 (t, 3H), 1.27 (m,2H), 1.38 (m, 2H), 1.61 (s, 6H), 3.0 (m, 2H), 4.41 (m, 2H), 5.98 (bs,1H), 7.31 (m, 2H), 8.06 (m, 2H), 10.86 (s, 1H) 12.39 (s, 1H). A01M2B27¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.78 (m, 2H), 0.86 (t, 3H), 1.27 (m,2H), 1.38 (m, 2H), 2.06 (m, 2H), 3.0 (m, 2H), 4.41 (m, 2H), 5.98 (bs,1H), 7.31 (m, 2H), 8.05 (m, 2H), 10.86 (s, 1H) 12.38 (s, 1H). A01M1B28¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.00 (t, 3H), 1.62 (s, 6H), 3.04 (m,2H), 4.42 (m, 2H), 6.01 (bs, 1H), 7.30 (m, 2H), 8.07 (m, 2H), 10.85 (s,1H) 12.38 (s, 1H). A55M1B28 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.00 (t,3H), 1.49 (d, J = 7.50 Hz, 3H), 1.55 (s, 3H), 1.58 (s, 3H), 3.01 (m,2H), 4.04 (q, 1H), 4.34 (m, 2H), 5.99 (bs, 1H), 7.48 (m, 3H), 7.87 (m,4H), 10.61 (s, 1H) 12.23 (s, 1H). A01M2B28 ¹H NMR (400 MHz, DMSO-d₆): δppm 0.78 (m, 2H), 0.99 (m, 3H), 2.06 (m, 2H), 2.98 (m, 2H), 4.56 (m,2H), 6.14 (bs, 1H), 7.33 (m, 2H), 8.07 (m, 2H), 10.88 (s, 1H) 12.09 (s,1H). A48M2B28 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.74 (m, 2H), 0.96 (m,3H), 2.03 (m, 2H), 2.96 (m, 2H), 3.80 (s, 2H), 4.45 (s, 2H), 5.68 (bs,1H), 6.06 (bs, 1H), 7.4-8.0 (m, 7H), 10.70 (s, 1H). A01M1B49 ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.06 (d, J = 6.55 Hz, 6H), 1.61 (s, 6H), 3.78 (m,1H), 4.41 (m, 2H), 5.66 (m, 1H), 7.31 (m, 2H), 8.06 (m, 2H), 10.85 (s,1H) 12.39 (s, 1H). A48M1B49 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.01 (d, J= 6.5 Hz, 6H), 1.56 (s, 6H), 3.76 (m, 1H), 4.29 (m, 2H), 5.66 (m, 1H),7.47 (m, 3H), 7.78 (m, 1H), 7.85 (m, 3H), 10.67 (s, 1H) 12.24 (s, 1H).A01M2B49 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.81 (m, 2H), 1.09 (d, J =6.64 Hz, 6H), 2.09 (m, 2H), 3.74 (m, 1H), 4.60 (m, 2H), 5.85 (m, 1H),7.36 (m, 2H), 8.10 (m, 2H), 10.92 (s, 1H) 11.76 (s, 1H). A01M1B55 ¹H NMR(400 MHz, DMSO-d₆): δ ppm 1.57 (m, 2H), 1.63 (s, 6H), 1.73 (m, 2H), 2.25(m, 1H), 2.64 (m, 2H), 3.43 (m, 2H), 4.56 (m, 2H), 6.75 (s, 1H), 7.27(s, 1H), 7.34 (m, 2H), 8.09 (m, 2H), 10.92 (s, 1H) 12.45 (s, 1H).A01M2B55 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.96 (m, 2H), 1.55 (m, 2H),1.71 (m, 2H), 1.82 (m, 2H), 2.34 (m, 1H), 2.75 (m, 2H), 3.48 (m, 2H),4.67 (m, 2H), 6.75 (s, 1H), 7.28 (s, 1H), 7.35 (m, 2H), 8.10 (m, 2H),10.98 (s, 1H) 12.19 (s, 1H).

EXAMPLE 21

Several compounds of the invention of formula (Ia) and (Ib), beingprepared as formerly reported, were also characterised by means ofHPLC/Mass techniques, hence through retention time (r.t.) and Mass[M+H]⁺

The operative conditions are reported below:

HPLC/MS Method 1

The HPLC equipment consisted of a Waters 2790 HPLC system equipped witha 996 Waters PDA detector and Micromass mod. ZQ single quadrupole massspectrometer, equipped with an electrospray (ESI) ion source. Instrumentcontrol, data acquisition and data processing were provided byMillennium 4.0 and MassLynx 3.5 software.

HPLC was carried out at 25° C. at a flow rate of 1 ml/min using a RP18Waters X Terra (4.6×50 mm, 3.5 Mm) column. Mobile phase A was ammoniumacetate 5 mM buffer (pH 5.5 with acetic acid/acetonitrile 95:5), andMobile phase B was H₂O/acetonitrile (5:95); the gradient was from 10 to90% B in 8 minutes then hold 90% B 2 minutes. The injection volume was10 μl.

The mass spectrometer was operated in positive and in negative ion mode,the capillary voltage was set up at 2.5 KV; the source temperature was120° C.; cone was 110 V; full scan, mass range from 100 to 800 amu wasset up.

HPLC/MS Method 2

The HPLC equipment consisted of a Waters 2790 HPLC system equipped witha 996 Waters PDA detector and Micromass mod. ZQ single quadrupole massspectrometer, equipped with an electrospray (ESI) ion source. Instrumentcontrol, data acquisition and data processing were provided byMillennium 4.0 and MassLynx 3.5 software.

HPLC was carried out at 25° C. at a flow rate of 1 ml/min using a RP18Waters X Terra (4.6×50 mm, 3.5 μm) column. Mobile phase A was ammoniumacetate 5 mM buffer (pH 5.5 with acetic acid/acetonitrile 95:5), andMobile phase B was H₂O/acetonitrile (5:95); the gradient was from 10 to90% B in 4 min then hold 90% B 1 minute. The injection volume was 10 μl.

The mass spectrometer was operated in positive and in negative ion mode,the capillary voltage was set up at 2.5 KV; the source temperature was120° C.; cone was 10 V; full scan, mass range from 100 to 800 amu wasset up.

HPLC/MS Method 3

Mass spectra were recorded on a Finnigan LCQ ion trap mass spectrometerusing the electrospray (ESI) ionization technique with positive andnegative ion detection. The mass spectrometer was directly connected toa SSP4000 HPLC system (Thermo Separation), equipped with an LcPalautosampler (CTC Analytics) and a UV 6000LP PDA detector (ThermoSeparation). Instrument control, data acquisition and processing wereperformed by using Xcalibur 1.2 software. HPLC analysis were carried outat room temperature at a flow rate of 1 ml/min using an RP C18 WatersX-Terra column (4.6×50 mm; 3.5 μm).

Mobile phase A was ammonium acetate 5 mM buffer (pH 5.5 with aceticacid):acetonitrile 90:10, and Mobile phase B was ammonium acetate 5 mMbuffer (pH 5.5 with acetic acid):acetonitrile 10:90; the gradient wasfrom 0 to 100% B in 7 minutes then hold 100% B for 2 minutes beforerequilibration. Total LC time is 12 minutes. The injection volume was 10μl. UV Detection was performed between 215 and 400 nm.

Ions were generated under the following conditions. ESI sprayer voltage4.0 kV, heated capillary temperature 255° C., sheath gas nitrogen with apressure of 5.0 Bar. A full scan detection mode (from 50 to 1000 amu)was used with an MS/MS analysis of the most intense ion (normalizedcollision energy: 35%).

UV Detection: 215-400 nm.

HPLC/MS Method 4

The HPLC system used (Alliance 2790, with thermostated autosampler anddivert valve LabPro, UV detector 2487 and satin interface, ZQ massspectrometer with ESI interface) is a product of Waters Inc., Milford,Mass. The chemiluminescent nitrogen detector (CLND) mod. 8060 is aproduct of ANTEK Instruments Inc., Houston, Tex. The liquid handlerMiniprep 75 is a product of Tecan Group Ltd., Maennedorf, Switzerland.

The chromatographic conditions used were as follows: The flow rate wasset at 1 mL/min. Two mobile phases (mobile phase A: 0.1% formic acid,mobile phase B: 0.1% formic acid in methanol) were employed to run in 10min a linear gradient from 5% B to 95% B, which was maintained for 2min, and followed by re-equilibration at 5% B for the next 3 minutes.Run time was 15 min. Injection volume 10 μL, autosampler temperature 25°C., detection wavelength 220 nm.

As reported in the following table VI, some other compounds of formula(Ia) and (Ib) were prepared, each identified through the aforementionedA-M-B coding system, and further characterised through HPLC/Mass,according to the experimental conditions being above reported.

TABLE VI Compound HPLC Method r.t. (min) [M + H]⁺ A01M1B09 3 4.60 386.0A01M1B10 3 3.52 388.0 A01M1B11 1 5.55 400.5 A01M1B16 1 2.82 415.5A01M1B18 1 3.06 455.5 A01M1B23 3 2.71 406.0 A01M1B24 3 5.05 434.0A01M1B25 3 3.10 376.0 A01M1B26 3 2.80 362.1 A01M1B29 1 4.00 431.5A01M1B30 1 3.39 402.4 A01M1B31 1 2.60 431.5 A01M1B32 3 6.07 430.0A01M1B33 3 3.67 416.0 A01M1B35 1 3.66 402.4 A01M1B36 1 2.70 401.5A01M1B37 1 4.75 404.4 A01M1B38 1 2.76 401.5 A01M1B40 1 2.74 475.5A01M1B41 3 4.75 510.1 A01M1B42 1 3.79 480.5 A01M1B46 3 2.68 419.0A01M1B49 3 3.87 360.0 A02M1B11 2 2.35 400.5 A02M1B16 2 1.09 415.5A02M1B18 2 1.16 455.5 A02M1B29 2 1.64 431.5 A02M1B30 2 1.36 402.4A02M1B31 2 0.96 431.5 A02M1B35 2 1.48 402.4 A02M1B36 2 1.01 401.5A02M1B37 2 1.96 404.4 A02M1B38 2 1.03 401.5 A02M1B40 2 1.01 475.5A02M1B42 2 1.59 480.5 A04M1B09 1 5.02 404.4 A04M1B10 1 3.77 406.4A04M1B11 1 5.57 418.5 A04M1B25 1 3.25 394.4 A04M1B27 1 4.72 392.4A04M1B28 1 3.68 364.4 A04M1B30 1 3.34 420.4 A04M1B33 1 3.88 434.5A04M1B34 1 3.40 447.5 A04M1B41 1 5.25 528.5 A04M1B49 1 4.18 378.4A05M1B11 1 6.03 418.5 A05M1B18 1 3.08 473.5 A05M1B29 1 4.30 449.5A05M1B30 1 0.72 420.4 A05M1B31 1 2.66 449.5 A05M1B35 1 4.00 420.4A05M1B36 1 2.83 419.4 A05M1B37 1 5.17 422.4 A05M1B38 1 2.79 419.4A05M1B40 1 2.82 493.5 A05M1B42 1 4.07 498.5 A06M1B11 1 6.09 416.9A06M1B16 1 3.17 431.9 A06M1B18 1 3.39 472.0 A06M1B29 1 4.42 447.9A06M1B31 1 2.99 447.9 A06M1B36 1 3.04 417.9 A06M1B39 1 3.15 447.0A06M1B40 1 3.08 492.0 A06M1B42 1 4.17 497.0 A07M1B11 2 3.07 450.5A07M1B16 2 1.78 465.5 A07M1B18 2 1.86 505.6 A07M1B29 2 2.36 481.5A07M1B30 2 2.11 452.4 A07M1B31 2 1.69 481.5 A07M1B35 2 2.24 452.4A07M1B36 2 1.72 451.5 A07M1B37 2 2.73 454.4 A07M1B38 2 1.71 451.5A07M1B40 2 1.73 525.5 A07M1B42 2 2.25 530.5 A10M1B11 1 3.83 388.5A10M1B16 1 2.56 403.5 A10M1B18 1 2.58 443.6 A10M1B29 1 3.76 419.5A10M1B30 1 3.13 390.5 A10M1B31 1 2.24 419.5 A10M1B37 1 4.45 392.5A10M1B38 1 2.35 389.5 A10M1B40 1 2.34 463.6 A10M1B42 1 3.54 468.6A12M1B09 1 4.43 348.5 A12M1B10 1 3.18 350.4 A12M1B25 1 2.71 338.4A12M1B28 1 3.08 308.4 A12M1B31 1 1.89 393.5 A12M1B33 1 3.40 378.5A12M1B41 1 4.80 472.6 A12M1B49 1 3.56 322.4 A13M1B09 1 4.24 346.4A13M1B10 1 2.98 348.4 A13M1B11 1 4.82 360.5 A13M1B25 1 2.52 336.4A13M1B28 1 2.86 306.4 A13M1B30 1 2.66 362.4 A13M1B31 1 1.86 391.5A13M1B33 1 3.22 376.5 A13M1B41 1 4.67 470.6 A13M1B49 1 3.37 320.4A14M1B09 1 3.80 332.4 A14M1B10 1 2.57 334.4 A14M1B11 4 8.32 346.2A14M1B30 1 2.28 348.4 A14M1B31 1 1.39 377.5 A14M1B33 1 2.87 362.4A14M1B34 1 2.41 375.4 A14M1B35 1 2.52 348.4 A14M1B41 1 4.30 456.5A14M1B49 1 2.94 306.4 A16M1B09 1 5.93 452.4 A16M1B10 1 4.78 454.4A16M1B11 1 6.43 466.5 A16M1B25 1 4.27 442.4 A16M1B28 1 4.73 412.4A16M1B30 1 4.32 468.4 A16M1B31 1 3.37 497.5 A16M1B32 1 5.20 496.5A16M1B33 1 4.82 482.5 A16M1B34 1 4.34 495.5 A16M1B35 1 4.60 468.4A16M1B49 1 5.15 426.4 A17M1B11 2 3.37 474.6 A17M1B16 2 2.29 489.6A17M1B18 2 2.33 529.7 A17M1B29 2 2.60 505.6 A17M1B30 2 2.39 476.5A17M1B31 2 2.08 505.6 A17M1B35 2 2.53 476.5 A17M1B36 2 2.08 475.6A17M1B37 2 3.01 478.5 A21M1B09 1 4.92 434.5 A21M1B10 1 3.78 436.5A21M1B25 1 3.33 424.5 A21M1B28 1 3.71 394.4 A21M1B31 1 2.66 479.6A21M1B33 1 3.90 464.5 A21M1B49 1 4.13 408.5 A22M1B09 1 5.54 418.5A22M1B10 1 4.65 420.5 A22M1B11 1 6.05 432.5 A22M1B25 1 3.81 408.5A22M1B27 1 5.27 406.5 A22M1B28 1 4.33 378.4 A22M1B30 1 3.86 434.5A22M1B31 1 2.92 463.6 A22M1B32 1 4.81 462.6 A22M1B33 1 4.40 448.5A22M1B34 1 3.90 461.5 A22M1B35 1 4.46 434.5 A22M1B41 1 4.11 542.6A22M1B49 1 4.77 392.5 A23M1B09 1 5.91 418.5 A23M1B10 1 4.67 420.5A23M1B11 1 6.45 432.5 A23M1B25 1 4.16 408.5 A23M1B27 1 5.56 406.5A23M1B28 1 4.62 378.4 A23M1B30 1 4.20 434.5 A23M1B31 1 3.21 463.6A23M1B32 1 5.13 462.6 A23M1B33 1 4.72 448.5 A23M1B34 1 4.24 461.5A23M1B35 1 4.49 434.5 A23M1B41 1 5.98 542.6 A23M1B49 1 5.05 392.5A24M1B09 1 5.02 411.5 A24M1B10 1 3.91 413.5 A24M1B28 1 3.87 371.5A24M1B31 1 2.73 456.6 A24M1B33 1 4.05 441.5 A24M1B49 1 4.28 385.5A25M1B09 1 4.65 397.5 A25M1B10 1 3.53 399.5 A25M1B25 1 3.13 387.5A25M1B28 1 3.48 357.4 A25M1B30 1 3.20 413.5 A25M1B31 1 2.26 442.5A25M1B33 1 3.47 427.5 A25M1B41 1 4.94 521.6 A25M1B49 1 3.91 371.5A26M1B09 1 3.87 349.4 A26M1B10 1 2.72 351.4 A26M1B28 1 2.62 309.4A26M1B33 1 3.00 379.5 A26M1B49 1 3.06 323.4 A27M1B09 1 5.34 401.5A27M1B10 1 4.13 403.4 A27M1B25 1 3.65 391.4 A27M1B31 1 2.85 446.5A27M1B33 1 4.22 431.5 A27M1B49 1 4.52 375.4 A30M1B09 1 4.78 368.5A30M1B10 1 3.53 370.4 A30M1B11 1 5.33 382.5 A30M1B25 1 3.04 358.4A30M1B27 1 4.45 356.4 A30M1B28 1 3.43 328.4 A30M1B30 1 3.13 384.4A30M1B31 1 2.27 413.5 A30M1B33 1 3.69 398.5 A30M1B34 1 3.21 411.5A30M1B35 1 3.38 384.4 A30M1B41 1 5.06 492.6 A30M1B49 1 3.91 342.4A48M1B09 3 5.30 432.1 A48M1B10 3 4.18 434.1 A48M1B23 3 3.38 452.1A48M1B24 3 3.78 480.1 A48M1B25 3 3.83 422.1 A48M1B26 3 3.48 408.2A48M1B30 3 4.00 448.2 A48M1B31 3 3.22 477.1 A48M1B32 3 4.28 476.3A48M1B33 3 4.23 462.1 A48M1B40 3 3.33 521.3 A48M1B41 3 4.72 556.2A48M1B46 3 3.43 465.1 A48M1B49 3 4.77 406.1 A53M1B09 1 3.10 417.5A53M1B28 1 2.02 377.5 A53M1B49 1 2.37 391.5 A54M1B09 1 5.87 436.4A54M1B10 1 4.65 438.4 A54M1B11 4 9.71 450.1 A54M1B25 1 4.14 426.4A54M1B28 1 4.60 396.4 A54M1B31 1 3.22 481.5 A54M1B33 1 4.70 466.5A54M1B34 1 4.20 479.5 A54M1B35 1 4.46 452.4 A54M1B41 1 5.93 560.6A54M1B49 1 5.05 410.4 A01M2B11 2 2.75 398.5 A01M2B16 2 1.40 413.5A01M2B18 2 1.50 453.5 A01M2B29 2 2.08 429.5 A01M2B30 2 1.71 400.4A01M2B31 2 1.27 429.5 A01M2B35 2 1.84 400.4 A01M2B36 2 1.31 399.2A01M2B37 2 2.33 402.4 A01M2B38 2 1.34 399.4 A01M2B40 2 1.34 473.5A01M2B42 2 1.93 478.5 A06M2B09 1 5.52 400.9 A06M2B11 1 6.04 414.9A06M2B16 1 2.95 429.9 A06M2B18 1 3.16 470.0 A06M2B29 1 4.57 445.9A06M2B30 1 3.82 416.9 A06M2B31 1 2.90 445.9 A06M2B35 1 4.08 416.9A06M2B36 1 2.94 415.9 A06M2B37 1 5.20 418.9 A06M2B38 1 3.00 415.9A06M2B40 1 3.03 490.0 A07M2B11 2 3.10 448.5 A07M2B16 2 1.80 463.5A07M2B18 2 1.90 503.5 A07M2B29 2 2.46 479.5 A07M2B30 2 2.13 450.4A07M2B31 2 1.71 479.5 A07M2B35 2 2.26 450.4 A07M2B36 2 1.74 449.4A07M2B37 2 2.75 452.4 A07M2B38 2 1.78 449.4 A07M2B40 2 1.76 523.5A07M2B42 2 2.29 528.5 A17M2B16 2 2.10 487.6 A17M2B18 2 2.17 527.6A17M2B29 2 2.73 503.6 A17M2B30 2 2.40 474.5 A17M2B31 2 2.01 503.6A17M2B35 2 2.55 474.5 A17M2B36 2 2.03 473.5 A17M2B37 2 3.05 476.5A17M2B38 2 2.07 473.5 A17M2B40 2 2.04 547.6 A17M2B42 2 2.55 552.6

The invention claimed is:
 1. A method for treating a cancer, the methodcomprising administering to a mammal in need thereof an effective amountof a compound represented by the following formula:

wherein R is a group —COR^(a), —CONHR^(a) or —CONR^(a)R^(b) whereinR^(a) and R^(b) are, each independently, hydrogen or an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl, C₃-C₆cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or;together with the nitrogen atom to which they are bonded, R^(a) andR^(b) may form an optionally substituted 5 or 6 membered heterocycleoptionally containing one additional heteroatom or heteroatomic groupselected among N, NH, O or S; and R₁ is tert-butyl; or apharmaceutically acceptable salt thereof.
 2. The method according toclaim 1 wherein the cancer is selected from the group consisting ofcarcinoma, squamous cell carcinoma, hematopoietic tumors of myeloid orlymphoid lineage, tumors of mesenchymal origin, tumors of the centraland peripheral nervous system, melanoma, seminoma, teratocarcinoma,osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicularcancer, and Kaposi's sarcoma.
 3. The method according to claim 1 furthercomprising subjecting the mammal in need thereof to a radiation therapyor chemotherapy regimen in combination with at least one cytostatic orcytotoxic agent.
 4. The method according to claim 1 wherein the mammalin need thereof is a human.
 5. A compound represented by the followingformula:

wherein R is a group —COR^(a), —CONHR^(a) or —CONR^(a)R^(b) whereinR^(a) and R^(b) are, each independently, hydrogen or an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl, C₃-C₆cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or;together with the nitrogen atom to which they are bonded, R^(a) andR^(b) may form an optionally substituted 5 or 6 membered heterocycleoptionally containing one additional heteroatom or heteroatomic groupselected among N, NH, O or S; and R₁ is tert-butyl; or apharmaceutically acceptable salt thereof.
 6. A compound of formula (Ia)according to claim 5, wherein R is a group —COR^(a) with R^(a) as4-fluorophenyl or cyclobutyl.
 7. A compound of claim 5, wherein any ofR^(a) and R^(b) is further substituted in one or more of their freepositions, by groups independently selected from halogen, nitro, oxogroups (═O), cyano, alkyl, perfluorinated alkyl, perfluorinated alkoxy,alkenyl, alkynyl, hydroxyalkyl, aryl, arylalkyl, heterocyclyl,cycloalkyl, hydroxy, alkoxy, aryloxy, heterocyclyloxy, methylenedioxy,alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, alkylideneaminooxy,carboxy, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, amino,ureido, alkylamino, dialkylamino, arylamino, diarylamino, formylamino,alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino,alkoxycarbonylamino, alkoxyimino, alkylsulfonylamino, arylsulfonylamino,formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl,heterocyclylcarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylthio and alkylthio.
 8. Acompound:N-[5-(2,2-dimethylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-4-fluorobenzamide;or a pharmaceutically acceptable salt thereof.
 9. A library of two ormore compounds of the following formula:

wherein R is a group —COR^(a),—CONHR^(a) or —CONR^(a)R^(b) wherein R^(a)and R^(b) are, each, independently, hydrogen or an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl, C₃-C₆cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or;together with the nitrogen atom to which they are bonded, R^(a) andR^(b) may form an optionally substituted 5 or 6 membered heterocycleoptionally containing one additional heteroatom or heteroatomic groupselected among N, NH, O or S; and R₁ is tert-butyl; or pharmaceuticallyacceptable salt thereof.
 10. A pharmaceutical composition comprising atherapeutically effective amount of a compound of formula (Ia), asdefined in claim 5, and at least one pharmaceutically acceptableexcipient, carrier and/or diluents.
 11. A pharmaceutical compositionaccording to claim 10 further comprising one or more chemotherapeuticagents.
 12. A product or kit comprising a compound of formula (Ia) asdefined in claim 5 or a pharmaceutical composition thereof as defined inclaim 10, and one or more chemotherapeutic agents.
 13. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compound,as defined in claim 5, and a chemotherapeutic agent selected from thegroup consisting of cytostatic or cytotoxic agents, antibiotic-typeagents, alkylating agents, antimetabolite agents, hormonal agents,immunological agents, interferon-type agents, cyclooxygenase inhibitors,matrixmetalloprotease inhibitors, telomerase inhibitors, tyrosine kinaseinhibitors, anti-grow factor receptor agents, anti-HER agents, anti-EGFRagents, anti-angiogenesis agents, farnesyl transferase inhibitors,ras-raf signal transduction pathway inhibitors, cell cycle inhibitors,cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors,typoisomerase II inhibitors and mixtures thereof.
 14. A product or kitcomprising a compound of claim 5, and a chemotherapeutic agent selectedfrom the group consisting of cytostatic or cytotoxic agents,antibiotic-type agents, alkylating agents, antimetabolite agents,hormonal agents, immunological agents, interferon-type agents,cyclooxygenase inhibitors, matrixmetalloprotease inhibitors, telomeraseinhibitors, tyrosine kinase inhibitors, anti-grow factor receptoragents, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents,farnesyl transferase inhibitors, ras-raf signal transduction pathwayinhibitors, cell cycle inhibitors, cdks inhibitors, tubulin bindingagents, topoisomerase I inhibitors, typoisomerase II inhibitors andmixtures thereof, as a combined preparation for simultaneous, separateor sequential use in anticancer therapy.
 15. The method according toclaim 1 wherein the cancer is a tumor.
 16. The method according to claim15, wherein the tumor is selected from the group consisting ofhematopoietic tumors of lymphoid lineage, hematopoietic tumors ofmyeloid lineage, tumors of mesenchymal origin, tumors of the central andperipheral nervous system, melanomas, seminomas, teratocarcinomas,osteosarcomas, thyroid follicular cancer, and Kaposi's sarcoma.